Devices and methods for treating subjects

ABSTRACT

One aspect of the present disclosure is directed to a device for providing light to the surface of a subject, comprising an array of a plurality of light emitting modules, wherein the plurality comprises four light emitting modules, each module of the plurality is flexibly connected to another module of the plurality, and two of the modules of the plurality comprise a polygonal perimeter having 4, 5, or 6 major sides, a light source, and a longest apex-to-apex dimension for a module of 5-50 millimeters, and, optionally, a non-adherent member configured to be adjacent to the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 120 as a continuationof U.S. patent application Ser. No. 16/008,899, titled “DEVICES ANDMETHODS FOR TREATING SUBJECTS,” filed Jun. 14, 2018, which claimspriority under 35 U.S.C. § 119(e) to U.S. Provisional Application Ser.No. 62/520,856, titled “DEVICES AND METHODS FOR TREATING SUBJECTS,”filed on Jun. 16, 2017, and to U.S. Provisional Application Ser. No.62/555,128, titled “DEVICES AND METHODS FOR TREATING SUBJECTS,” filed onSep. 7, 2017. Each of these applications is herein incorporated byreference in its entirety for all purposes.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The invention relates to devices and methods for providing irradiationto a subject.

2. Background

The delivery of light can be used to modulate the level of pathogens ina subject, for example, in a burn, and to modulate healing.

SUMMARY

Devices and methods described herein can be configured as a flexible(body conforming) bandage and therefore can be placed directly on theskin surface and under the wound dressing or other bandage material orwound healing technology.

Devices and methods described herein provide advantages including: 1)mono- or multispectral based low-level irradiance wound care that cantreat skin/wound infections, reduce the bacterial and fungal bio-burdenof wounds, including biofilms, and stimulate the healing of acute andchronic skin ulcers and, 2) deployment of a novel wound careillumination system that can provide irradiance via a conformable,wearable bandage or dressing with portable power supply.

Accordingly, in one aspect the invention features a method of treating asubject, the method comprising:

irradiating the subject with light having a wavelength between 380 nmand 500 nm, for example, at 405 nm, at.25 to 25 milliWatts/cm², whereinthe irradiation is for a time sufficient to treat a subject, and whereintreating comprises:

a) treating a subject at risk for a pathogen infection;

b) treating a subject having a pathogen infection;

c) preventing the infection by a pathogen;

d) reducing the level of a pathogen;

e) reducing the virulence of a pathogen in the subject, for example,reducing its ability to damage the subject, slowing the growth of thepathogen, or reducing the release of a toxin by the pathogen;

f) reducing or otherwise ameliorating an unwanted manifestation ofinfection by a pathogen;

g) reducing the level or transmission of a transmissible nucleic acid,for example, a plasmid or an RNA, by a pathogen, for example, to asecond pathogen; or

h) modulating, for example, inhibiting, reducing, or degrading thestructure or integrity an extracellular matrix;

i) modulating the microbiome of the subject, for example, at the site ofirradiation or at site outside the site of irradiation, for example,reducing one or more members of a polymicrobial community; or

j) irradiating a site at which a device, for example, a catheter orconductor, enters the subject's body.

In an embodiment, the method further comprises treating a subject atrisk for a pathogen infection.

In an embodiment, the method further comprises increasing the porosityof a biofilm, for example, increasing the porosity to a drug, forexample, an antibiotic. In an embodiment porosity refers to the abilityof an antibiotic drug molecule to pass into or through a biofilm. Inembodiments increased porosity increases the ability of an appliedantibiotic to come into contact or kill a bacterium.

In an embodiment, the subject has a burn, for example, a burn that isgreater than a Grade 1 burn, for example, a superficial first-degreeburn of the epidermis, or outer layer of skin.

In an embodiment, the site irradiated comprises entry point of a medicaldevice, for example, the point of entry of a conduit, catheter, PICline, Hickman catheter.

In an embodiment the light has a wavelength 405 nm+/−10 nm.

In an embodiment, the light is provided at between 0.25 and 25milliWatts/cm².

In an embodiment, the irradiation is administered at a place other thana health care facility, for example, a hospital, clinic, or physician'soffice, for example, the irradiation is administered after discharge orexit from a health care facility, for example, a hospital, clinic, orphysician's office.

In an embodiment, the irradiation is provided by a device comprising apower source, for example, a wearable power source.

In an embodiment, irradiation is provided as a plurality of periods orpulses wherein the pulses are separated by intervening periods whenirradiation is not provided, for example, darkness.

In another embodiment, the invention features a method of treating asubject having a burn, the method comprising:

irradiating the subject with light having a wavelength between 380 nmand 500 nm at 0.25 to 25 milliWatts/cm²,

wherein the irradiation is for a time sufficient to prevent infection ofthe subject by a pathogen reducing the level of a pathogen (for example,in the burn or systemically), or reducing or otherwise ameliorating anunwanted manifestation of infection by a pathogen (for example, in theburn or systemically) in a subject.

In another aspect, the invention features, a device for providing lightto the surface of a subject, the device comprising:

a) an array of a plurality of light emitting modules,

-   -   each module of the plurality being flexibly connected to another        module of the plurality, and    -   each module of the plurality being capable of emitting light,

wherein the array is configured to conform to the surface of thesubject.

In an embodiment the device comprises b) light or energy source.

In an embodiment the device comprises c) a connector for transmittingcurrent or light from b to a.

In an embodiment two or more modules of the plurality are configured soas to be able to emit light simultaneously. In an embodiment two or moremodules of the plurality are configured so as to be able to emit lightat different wavelengths, intensities, or at different times.

In an embodiment, the array of modules is flexible, stretchable, or canbe molded to a surface.

In an embodiment, the array of modules can be bent to conform to surfaceor body part of the subject and when bent to a conforming shape retainsthe conforming shape.

In an embodiment, each module of the plurality is configured to providelight at 0.25 to 25 milliWatts/cm², for example, at the surface of thesubject.

In an embodiment, the device comprises 2 to 400; 3 to 200; 4 to 100; 5to 50; 10 to 40; or 20 to 30, modules.

In an embodiment, a module, for example, a module with a hexagonalperimeter, has a longest apex to apex distance, or a longest dimensionof 22.5 millimeters.

In an embodiment, modules are present in the array having an X axis anda Y axis and the array is at least 1, 3, 10, or 100 modules in lengthalong the X axis and at least 1, 3, 10, or 100 modules in length alongthe Y axis.

In an embodiment, the device further comprises a sensor.

In an embodiment, the sensor is connected, for example, wirelesslyconnected, with a processor or computer.

In an embodiment, responsive to a signal from the sensor, the device, ora processor or computer connected thereto, provides a signal, forexample, an alert, to another device or a person, for example, thesubject or a caregiver.

In an embodiment, the irradiation is provided by a device comprising abattery.

In another aspect, the invention features, a device for providing lightto the surface of a subject, comprising:

(a) an array of a plurality of light emitting modules,

wherein each module of the plurality is flexibly connected to anothermodule of the plurality; and each module of the plurality comprises

-   -   (i) a light emitting device,    -   (ii) an internally reflective layer configured to receive light        from the light emitting device,    -   (iii) a port for emission of light from the internally        reflective layer,    -   (iv) a diffusing member, and    -   (v) a polygonal perimeter,    -   wherein the array,        -   (i) is configured to conform to the surface of the subject,            and        -   (ii) comprises at least 4 modules;

(b) a light or energy source; and

(c) a connector for transmitting current or light from (b) to (a).

In an embodiment, each module of the plurality comprises a hexagonalperimeter.

In an embodiment, each module of the plurality is configured to providelight at 0.25 to 25 milliWatts/cm², for example, at the surface of thesubject.

In an embodiment, each module of the plurality is configured to providelight having a wavelength between: 380 nm and 500 nm; 390 nm and 430 nm;and 395 nm and 415 nm.

In another aspect, the method features, a device for treating a subject,the device comprising:

a wound surface contact layer;

a rigid-flex circuit layer configured in a gapped-geometric pattern foreven distribution of light and flexibility to conform to body surfacesof a wound; and

a backing layer which, with the wound surface contact layer, isconfigured to enclose or substantially enclose the rigid-flex circuitlayer therein.

In an embodiment, the rigid-flex circuit layer is a gapped-hexagonpattern.

In another aspect, the invention features a device for providing lightto the surface of a subject, comprising: (a) an array of a plurality oflight emitting modules, wherein (i) the plurality comprises four lightemitting modules; (ii) each module of the plurality is flexiblyconnected to another module of the plurality; (iii) two of the modulesof the plurality comprise: (A) a polygonal perimeter having 4, 5, or 6major sides; (B) a light source; (C) a longest apex-to-apex dimensionfor a module of 5-50 millimeters; and (optionally) (b) a non-adherentmember configured to be adjacent to the subject.

In another aspect, the invention features a device for providing lightto the surface of a subject, comprising: (a) an array of a plurality oflight emitting modules, wherein (i) the plurality comprises four lightemitting modules; (ii) each module of the plurality is flexiblyconnected to another module of the plurality; (iii) the modules of theplurality each comprise: (A) a polygonal perimeter having 6 major sides;(B) a light emitting diode; (C) an internally reflective memberconfigured to receive light from the light emitting diode, (D) a portfor emission of light from the internally reflective member, and (E) adiffusing member. (F) a longest apex-to-apex dimension for a module of20+/−5 millimeters; and (b) a non-adherent member configured to beadjacent to the subject.

In another aspect, the invention features a method for providing lightto a subject comprising: providing light to the surface of a subjectwith a device, comprising: (a) an array of a plurality of light emittingmodules, wherein (i) the plurality comprises four light emittingmodules; (ii) each module of the plurality is flexibly connected toanother module of the plurality; (iii) two of the modules of theplurality comprise: (A) a polygonal perimeter having 4, 5, or 6 majorsides; (B) a light source; (C) a longest apex-to-apex dimension for amodule of 5-50 millimeters; and (optionally) (b) a non-adherent memberconfigured to be adjacent to the subject, thereby providing light to thesubject.

Devices and methods described here include those directed to aLow-Irradiance Metronomic Biostimulation (LIMB) System. They provide anovel, wearable technology-essentially a “bandage”-. The device caninclude integrated electronics that can easily be deployed inenvironments ranging from the battlefield to community wound-healingclinics. In embodiments, the core technology and light delivery methoddescribed herein provide two functionalities. First, antimicrobialactivity—the device's visible blue irradiation (non-ultraviolet) reducesbioburden and has the potential to manage infections without the needfor additional pharmacological interventions. Second, using the sameenergy delivery portal, visible red and near infrared wavelengths, canbe delivered at low-irradiance continuously over extended periods(because the device is wearable), is used to also aid in infectioncontrol, while also potentially accelerating the healing of soft-tissueand bone traumatic injuries.

The devices and methods disclosed herein provide a flexible array thatcan conform closely to the subject's body and provide illumination. Thedevices and methods disclosed herein minimize the need for removal ofbandages and dressings to provide the therapy, which makes the woundsite less susceptible to infection since the wound site is not exposedas frequently to open environments that may contain a bacteria, fungus,spore that can cause infection. In embodiments, devices disclosed hereinare configured as a flexible bandage or element that can be applied fordays/weeks. As a result, the LIMB system can be applied to injuredpersonnel in both ambulatory and inpatient settings throughout LevelI-IV trauma centers and significantly reduce the risk ofcommunity-acquired and nosocomial infections typically associated withpatient handling and transport.

A significant advantage of devices and methods described herein is theavoidance of high-powered light sources that are relatively expensive,and require a specialized medical facility and staff to operate andmaintain, requiring patients to make frequent trips to their clinic.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

Various aspects of at least one embodiment are discussed below withreference to the accompanying figures, which are not intended to bedrawn to scale. The figures are included to provide an illustration anda further understanding of the various aspects and embodiments, and areincorporated in and constitute a part of this specification, but are notintended as a definition of the limits of any particular embodiment. Thedrawings, together with the remainder of the specification, serve toexplain principles and operations of the described and claimed aspectsand embodiments. In the figures, each identical or nearly identicalcomponent that is illustrated in various figures is represented by alike numeral. For purposes of clarity, not every component may belabeled in every figure. In the figures:

FIG. 1(a) illustrates a top view of a device having a single segmentwithout foam.

FIG. 1(b) illustrates a perspective view of the device having a singlesegment without foam.

FIG. 2 illustrates a side view of a hexagon light guide and electronicslayout.

FIG. 3 illustrates a top view of the hexagon light guide and electronicslayout.

FIG. 4 illustrates a view of side-emitting LED in relation to apolygonal light guide.

FIG. 5 illustrates a fiber optic light guide, used for photodynamictherapy applications.

FIG. 6(a) illustrates a solid body light guide approach foreven-illumination phototherapy applications.

FIG. 6(b) illustrates an example implementation of the solid body lightguide design.

FIG. 6(c) illustrates a power pack corresponding to the exampleimplementation of the solid body light guide design.

FIG. 7(a) illustrates a top view of an LED array approach to flexiblelight delivery.

FIG. 7(b) illustrates a side view of the LED array approach to flexiblelight delivery.

FIG. 8 illustrates discrete light guides.

FIG. 9 illustrates an LED and hexagonal light guide array design.

FIG. 10 illustrates an LED and octagon light guide array design.

FIG. 11 illustrates flat connections between light guides of an LED andlight guide array.

FIG. 12 illustrates multiple flex connections between components of anLED and light guide array.

FIG. 13 illustrates a bar graph showing the viability of MRSA clinicalisolates following exposure to 75 J/cm² LIMB system at varyingirradiances and exposure durations.

FIG. 14 illustrates a graph showing the viability of MRSA clinicalisolates following exposure to the LIMB system continuously for 24 hoursat varying irradiances.

FIG. 15 illustrates a graph showing the delivery of a single cycle of405 nm LIMB system over a 24 hour time period at irradiances of 1.39mW/cm², 2.78 mW/cm², and 5.56 mW/cm² on cultures of P. aeruginosa ingrowth conditions of 37° C. and 5% CO₂.

FIG. 16 illustrates graph showing the delivery of a single 24-hour cycleof LIMB system at fluences of: 60 J/cm²; 120 J/cm² and 240 J/cm², andexposure to ciprofloxacin (5 mg/L) on cultures of P. aeruginosa ingrowth conditions of 37° C. and 5% CO₂.

FIG. 17 illustrates a bar graph showing the delivery of a single cycleof 405 nm LIMB system over a 24 hour time period at fluences of 120J/cm²; 240 J/cm² and 360 J/cm² on P. aeruginosa biofilms previouslygrown for 24 hours at 37° C. and 5% CO₂.

FIG. 18 illustrates the delivery of a single cycle of the LIMB systemover a 24 hour time period at fluences of 120 J/cm²; 240 J/cm²; and 360J/cm², as well as ciprofloxacin concentrations of 5 mg/L; 500 mg/L; and5 g/L on P. aeruginosa biofilms previously grown for 24 hours at 37° C.and 5% CO₂.

FIG. 19 illustrates the quantitative analysis of Live/Dead ConfocalMicroscopy Staining of mature P. aeruginosa and MRSA biofilms exposed toa single LIMB system treatment over 18 hours.

FIG. 20 illustrates a Live/Dead Staining Assay of MRSA (A-B) and P.aeruginosa (C-D) following LIMB system treatment. A) MRSA and C) P.aeruginosa Control Groups, Receiving Sham Light Treatment; B) MRSA andD) P. aeruginosa following the LIMB system over 18 hours. (Greenindicates intact cell membrane and Red indicates damaged/lysedmembranes.)

FIG. 21 illustrates delivery of a single cycle of 405 nm LIMB systemover a 24 hour time period at fluences of 240 J/cm²; and 480 J/cm² inthe presence and absence of Ciprofloxacin on P. aeruginosa biofilmspreviously grown for 24 hours at 37° C. and 5% CO₂.

FIG. 22 depicts an example of a hexagon electronics and light guidearray.

FIG. 23 depicts an example of the hexagon electronics and light guidearray from a top view with the most immediate layers near theskin/wound.

FIG. 24 depicts an example of a hexagon electronics and light guidearray configured for use in a NPWT vacuum dressing.

FIG. 25 depicts an example of a hexagon electronics and light guidearray.

FIG. 26 depicts an example of a hexagon electronics and light guidearray embedded with a NPWT vacuum dressing.

FIG. 27 depicts an example of a schematic diagram illustrating lightbehavior at a material boundary.

FIG. 28 depicts an example of a schematic diagram of TIR conditionswhere n_(f)<n_(i).

FIG. 29 depicts an example of a schematic diagram of disrupting TIRwithin an LGF.

FIG. 30 depicts an example of a schematic diagram of microstructure sizeand location.

FIG. 31 depicts an example of a schematic diagram of microstructure sizeand location.

FIG. 32 depicts an example of a schematic view of multiple-sided lightinput sources.

FIG. 33 depicts an example of a schematic view of an LGF, a combinationof an embossed structure coating with a substrate film.

FIG. 34 illustrates a top view of multiple hexagons connected by thinwire according to an embodiment.

FIG. 35 illustrates a top view of a flat flexible cable according to anembodiment.

FIG. 36 illustrates a top perspective view of another flat flexiblecable according to an embodiment.

FIG. 37 illustrates a layout of a back plane connection layout accordingto an embodiment.

FIG. 38 illustrates a layout of a back plane connection layout accordingto another embodiment.

FIG. 39 illustrates shows a layout design for a Flat Flexible Circuitaccording to an embodiment.

DETAILED DESCRIPTION OF THE INVENTION

Examples of the methods and systems discussed herein are not limited inapplication to the details of construction and the arrangement ofcomponents set forth in the following description or illustrated in theaccompanying drawings. The methods and systems are capable ofimplementation in other embodiments and of being practiced or of beingcarried out in various ways. Examples of specific implementations areprovided herein for illustrative purposes only and are not intended tobe limiting. In particular, acts, components, elements and featuresdiscussed in connection with any one or more examples are not intendedto be excluded from a similar role in any other examples.

Also, the phraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. Any references toexamples, embodiments, components, elements or acts of the systems andmethods herein referred to in the singular may also embrace embodimentsincluding a plurality, and any references in plural to any embodiment,component, element or act herein may also embrace embodiments includingonly a singularity. References in the singular or plural form are nointended to limit the presently disclosed systems or methods, theircomponents, acts, or elements. The use herein of “including,”“comprising,” “having,” “containing,” “involving,” and variationsthereof is meant to encompass the items listed thereafter andequivalents thereof as well as additional items.

References to “or” may be construed as inclusive so that any termsdescribed using “or” may indicate any of a single, more than one, andall of the described terms. In addition, in the event of inconsistentusages of terms between this document and documents incorporated hereinby reference, the term usage in the incorporated features issupplementary to that of this document; for irreconcilable differences,the term usage in this document controls.

Definitions

A polygonal perimeter, as that term is used herein, refers to a shapehaving a perimeter with at least three sides, for example, at leastthree major sides. In an embodiment, each of the major perimeter sidesis longer than any minor perimeter side present. In an embodiment, amajor side is straight or linear but in embodiments it can includeirregularities, or features formed by connection to another element, forexample, a light emitter. In an embodiment, each major perimeter sidediffers in length from the other minor perimeter sides by no more than50, 40, 30, 20, 10, or 5%. In the case of a regular polygonal majorperimeter sides are of equal length and the apices of equal angle. Apolygonal perimeter be made up of a single unit or more than onesegment, for example, a regular hexagonal perimeter can be formed by twohalf regular hexagonal perimeters.

A hexagonal perimeter, as that term is used herein, refers to a shapehaving a perimeter with six major sides. Each of the major perimetersides is longer than any minor perimeter side present. In an embodiment,a major side is straight or linear but in embodiments it can haveirregularities, or features formed by connection to another element, forexample, a light emitter. In an embodiment, each major perimeter sidediffers in length from the other minor perimeter sides by no more than50, 40, 30, 20, 10, or 5%. In an embodiment, a hexagonal perimeter hassix perimeter sides and six apices. In the case of a regular hexagonalperimeter there are six major perimeter sides of equal length, sixapices, and no minor perimeter sides. In an embodiment, a hexagonalperimeter has six major perimeter sides and one or more minor perimetersides. For example, one apex of a hexagonal perimeter is replaced with aminor perimeter side, which can be visualized, for example, as a regularhexagon with one apex clipped off (and replaced by a minor perimeterside and two apices. A hexagonal perimeter be made up of a singleelement or more than one elements, for example, a regular hexagonalperimeter can be formed by two half regular hexagonal perimeters.

A triangular perimeter, as that term is used herein, has three majorperimeter sides but is otherwise analogous to a hexagonal perimeter.Generally, a polygonal perimeter can have X major sides, for example,with X equal to 3, 4, 5, 7, 8, 9, 10, 11 or 12, with other parametersanalogous to those of a hexagonal perimeter.

Fluence, or total fluence, as those terms are used herein, refer to astream of particles or photons crossing a unit area, usually representedin particles per second.

Irradiance, as that term is used herein, refers to the radiant flux(power) received by a surface per unit area. The SI unit of irradianceis the watt per square meter (W/m²), or Jules/cm² sec.

Burn categories, as used herein, are defined as follows:

First-degree or Grade 1 (superficial) burn, as that term is referred toherein, is a burn that affects only the epidermis, or outer layer ofskin. The burn site is red, painful, dry, and with no blisters. Mildsunburn is an example. Long-term tissue damage is rare and usuallyconsists of an increase or decrease in the skin color;

Second-degree or Grade 2 (partial thickness) burns, as that term isreferred to herein, is a burn that involves the epidermis and part ofthe dermis layer of skin. The burn site appears red, blistered, and maybe swollen and painful;

Third-degree or Grade 3 (full thickness) burn, as that term is referredto herein, is a burn that destroys the epidermis and dermis and may gointo the subcutaneous tissue. The burn site may appear white or charred;and

Fourth-degree or Grade 4 burns, as that term is referred to herein, is aburn that damages the underlying bones, muscles, and tendons. There isno sensation in the area since the nerve endings are destroyed.

Subject, as that term is used herein, refers to a human or a non-humananimal. Exemplary non-human animals include dogs, cats, monkeys,rodents, and domestic animals, for example, horses, cows, pigs, goats,and oxen.

Symmetry value, as used herein, relates to the relative duration ofperiods of irradiation and intervening periods. Symmetry value can bedetermined over a single cycle of one period of irradiation and oneintervening period or over a plurality of cycles. Symmetry value isexpressed as x:y, wherein x is the duration of period(s) of illuminationand y is the duration of intervening period(s). A symmetry value of50:50 means that the duration of the period(s) irradiation is equal tothe duration of the intervening period(s). A symmetry value of 10:100means that the duration of the period(s) irradiation is equal to onetenth the duration of the intervening period(s). The symmetry value canremain constant over a treatment or can change. An increase in symmetryvalue means a relative increase in the duration of the irradiationperiod(s) and a decrease in symmetry value means a relative decrease inthe duration of irradiation period(s). A pulse or period of illuminationcan have any of a variety of wave forms, for example, a square wave or asinusoidal wave.

Overview

Devices and methods described herein can be configured as a flexible(body conforming) bandage and therefore can be placed directly on theskin surface and under the wound dressing or other bandage material orwound healing technology, for example, vacuum-dressing for continuous24-hr/7-day-a-week treatment.

Devices and methods described herein provide advantages to current woundcare phototherapy illumination technologies including: 1)multispectral-based continuous low-level irradiance wound care that cantreat skin/wound infections, reduce the bacterial and fungal bio-burdenof wounds, including biofilms, and stimulate the healing of acute andchronic skin ulcers and, 2) deployment of a novel wound careillumination system that can provide the continuous low-level irradiancevia a conformable, wearable bandage or dressing with portable powersupply.

Devices and methods described herein comprise a flexible light-emittingbandage or element that is highly-conformable to body contours andprovides extended periods of illumination in an inpatient or ambulatorysetting. In embodiments, the core technology is engineered for woundcare healing and provides one or both of two functionalities that areprinciple to continuous low-level irradiance wound care. First, thedevice can emit low-level short wavelength illumination such as bluelight (405 nm) or short-duration pulses of UV-B (280-315 nm) or UV-C(315-400 nm) to reduce bio-burden to manage/avoid infection. Second, thedevice, using the same light delivery portal as the short wavelengthsource can deliver a combination of visible and near infraredwavelengths shown to accelerate wound healing. Other embodiments includetwo separate bandages or devices; one focused on antimicrobial therapy(reducing bio-burden) and another focused on wound healing.

In an embodiment wound care light delivery devices (or illuminationsources) have integrated into a bandage that can be placed beneath acompression dressing and enabled for inpatient or ambulatory (includinghome-based) continuous low-irradiance therapy. This device can aid acutewounds but can also provide significant clinical benefit to chronicwounds by allowing a chronic wound to reduce bacterial bio-burdenwithout the use of antibiotics. Additional benefits of this system arethat it allows illumination therapy to be administered continuously forextended periods of time in the comfort of the patient's home, and amongseniors, who are often poly-pharmacy, this would 1) reduce the untowardeffects of oral antibiotics, 2) avoid drug-drug interactions, 3) providea means to stimulate healing of chronic wounds and 4) avoid the need forfrequent travel to facilities to receive care.

An array of light emitting modules can be configured for coupling toanother array. Thus, an end user can select from a plurality of arraysfor combination for a particular indication or subject. For example, 2,3, 4, 5 or more arrays can be coupled. The array is configured to have abend radiance that allows close adherence to the curvature of thesurface being treated. In some embodiments, in has a bend radius of 5mm.

Methods and devices described herein can treat subjects having abiofilm, for example, to kill pathogens that might otherwise beprotected from a therapy by a biofilm. Patients with skin-relatedinfections (acute skin wounds, chronic skin ulcers and patients at highrisk for developing skin ulcer, for example, diabetics) can be treated.Because the technology prevents biofilm formation, beneficial resultsmay be achieved in connection with subjects of lost barrier, such asburn patients, to prevent the formation of biofilm. In the prevention ofbiofilm formation, the technology can be used instead of antibiotics. Inthe setting of a burn patient with a dirty wound, this technology can beused with a systemic antibiotic.

Methods and devices described herein can be used to treatimmunocompromised subjects. In an embodiment a method or devicedescribed herein can be used to treat a subject having hepaticimpairment or renal impairment, for example, hepatic or renal impairmentassociated with or due to the use of a 3rd or 4th generation antibiotic.

Wavelengths of Light Biostimulation: An Overview

Photobiomodulation, also referred to as, “biostimulation,” as that termis used herein, refers to the process of illuminating tissues with aspecific wavelength of light at a low intensity and with low power overextended periods of time. When using the appropriate dosages,wavelengths, and intensities, the applications of biostimulation providepatients with an effective and safe method of managing infection rateswhile promoting skin, soft tissue, and bone regeneration. Specificwavelengths within the visible blue (400-470 nm), visible red (620-700)and infrared (700-1000 nm) spectra are microbiocidal, accelerate woundhealing, and can be used intermittently or continuously for extendedperiods of time without engendering drug resistance.

Short Wavelength Biostimulation:

There is a significant body of evidence that has evaluated the use ofbiostimulation within the ultraviolet (UV) and visible blue wavelengthsfor their microbiocidal effects on a variety of multiple drug resistantorganisms (MDROs). UV biostimulation (100-400 nm) is a commonly-usedsterilization technique in clinical laboratories and healthcaresettings, and has been validated in multiple studies for itscapabilities to sterilize wound surfaces. Prophylactic UV-C (200-280 nm)light treatment can be used for infections developing inhighly-contaminated superficial cutaneous mouse wounds contaminated withPseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus(MRSA). For both bacterial infections, UV-C light significantly reducedthe bacterial burden in comparison to untreated wounds, while alsoincreasing the survival rate of P. aeruginosa-infected mice (58%) andthe wound-healing rate of MRSA-infected mice (31%). Despite itsbactericidal properties, there is a degree of collateral damageassociated with extended exposure to short-wavelength UV biostimulation,such as carcinogenicity and impaired wound healing.

Due to UV light's carcinogenic nature and ability to cause direct damageto host cells that inhibits wound healing, administration ofbiostimulation using wavelengths within the visible blue light (400-470nm) spectrum has been proven to be efficacious in both its bactericidaleffects in addition to its wound healing capabilities. Furthermore,based upon its mechanism of action, blue light biostimulation obviatesthe collateral damage commonly associated with UV light exposure and ismuch less detrimental to human cells. The antimicrobial mechanism ofvisible blue biostimulation involves the photoexcitation of endogenousporphyrins within pathogens, and, subsequently, the generation ofreactive oxygen species (ROS), which are in effect toxic to bacterialcells and biofilms. Exposure to a 405 nm LED array has a phototoxiceffect on a variety of bacteria that are highly prevalent incommunity-acquired and nosocomial infections, including Gram-positivebacteria: MRSA, Staphylococcus epidermidis, Streptococcus pyogenes,Clostridium perfringens, and Gram-negative bacteria: Acinetobacterbaumannii, Pseudomonas aeruginosa, Escherichia coli, Proteus vulgarisand Klebsiella pneumonia. Visible blue light (415 nm+/−10 nm) therapycan be used for eliminating community-acquired MRSA infection in skinabrasions of mice, and has been shown to produce a 2.0-log₁₀ (99.0%)bacterial inactivation in abrasions after one dose of light administeredover 30 minutes. On top of its bactericidal effects, further evidenceindicates that visible blue biostimulation enables a significantreduction of biofilm formation both prophylactically and in response totrauma. 415 nm blue light has antimicrobial properties on biofilms ofAcinetobacter baummanii.

Proliferative Effects of Long-Wavelength Biostimulation:

Biostimulation using longer wavelengths in both the visible red (620-700nm) and near-infrared (NIR; 700-1000 nm) range significantly acceleratestissue repair in bone, skin, muscle and nerves, as well as stimulatingboth angiogenesis and collagen deposition. Furthermore, it has beendocumented to regulate gene expression that directly promotes cellproliferation by suppression of apoptosis, in addition to regulating theexpression of genes related to cell migration and remodeling, DNAsynthesis and repair, and extracellular matrix deposition. Amongpublished studies, the most prevalently cited indication forbiostimulation is directed towards its capabilities of acceleratinggranulation and re-epithelialization of acute and chronic skin wounds.In patients with diabetic foot ulcers, biostimulation accelerated thehealing process of chronic diabetic foot ulcers, and biostimulationusing visible red wavelengths shortened the time period needed toachieve complete healing by as much as 21 days, compared to controltrials receiving traditional standards of care. The combination ofvisible red and IR wavelength biostimulation on diabetic leg ulcerpatients results in rapid granulation and healing of diabetic ulcersthat failed to respond to other forms of treatment.

In addition to rapid skin regeneration, biostimulation accelerates bonehealing, as well as restoring the functional recovery of nerve andmuscle tissue following traumatic injury. Infrared (830 nm)biostimulation can be used to treat closed bone fractures in the humanwrist and hand. NIR (808 nm) biostimulation promotes the recovery andnerve regeneration of post-traumatic nerve injuries on a sciatic nervecrush rat injury model. NIR (808 nm) biostimulation promotes muscleregeneration and vascular perfusion in Wistar rats that underwentcryolesion of the tibialis anterior muscle. Biostimulation significantlyreduces the lesion percentage area in the injured muscle, and increasesmRNA levels of the transcription factors MyoD and myogenin and thepro-angiogenic vascular endothelial growth factor. Moreover,biostimulation decreases the expression of the profibrotic transforminggrowth factor TGF-β mRNA and reduced type I collagen deposition.

Multispectral Biostimulation:

The bactericidal properties of the lower wavelengths with the softtissue and bone regeneration properties of the longer wavelengths can becombined to provide more favorable therapeutic outcomes thanmonochromatic biostimulation.

In embodiments, devices and methods described herein provide thesewavelengths at an optimal dosage and: 1) ensure a conducive woundenvironment, 2) provide biostimulation to stimulate healing bone andsoft tissue regeneration of devascularized tissues of as a result oftrauma-induced and combat-related injuries, and 3) reduce the untowardeffects of oral and intravenous antibiotics.

Low-Irradiance Metronomic Biostimulation (LIMB) System:

There is a wide variety of illumination devices that providebiostimulation in use currently in both clinical trials andcommercially; primarily these are classified as medical lasers or LEDmedical lasers. The medical lasers in current use range significantlyfrom large desktop-computer sized lasers to handheld LED devices.Nonetheless, clinical trials are typically similar in that the subjectsreceiving biostimulation are exposed to monochromatic (one wavelength)light at high irradiances (>100 mW/cm²) over a short duration of 10-20minutes, ultimately requiring subjects to frequently travel to treatmentclinics to receive therapy.

Embodiments of the present disclosure are directed to a Low-IrradianceMetronomic Biostimulation (LIMB) System: a novel, wearabletechnology—essentially a “bandage”—with integrated electronics that caneasily be deployed in environments ranging from the battlefield tocommunity wound-healing clinics. In embodiments, the core technology andlight delivery method described herein provide two functionalities.First, antimicrobial activity—the device's visible blue irradiation(non-ultraviolet) reduces bio-burden and has the potential to manageinfections without the need for additional pharmacologicalinterventions. Second, using the same energy delivery portal,visible-red and near-infrared wavelengths can be delivered atlow-irradiance continuously over extended periods (because the device iswearable), and is used to also aid in infection control, while alsopotentially accelerating the healing of soft-tissue and bone traumaticinjuries.

An additional factor of the LIMB system is that it also addresses thelimitations of prior irradiance-based technologies that have been usedin infection control and wound management. While current technologiesrequire removal of bandages and dressings to provide the therapy, whichmakes the wound site more susceptible to infection, embodiments of theLIMB system are configured as a flexible bandage that can be applied fordays/weeks. As a result, the LIMB system can be applied to injuredpersonnel in both ambulatory and inpatient settings throughout LevelI-IV trauma centers and could significantly eliminate the risk ofcommunity-acquired and nosocomial infections typically associated withpatient handling and transport.

Pathogens and Irradiation

In addition to enabling biostimulation application into acute caresettings, devices and methods described herein also address thelimitations of prior irradiance-based technologies that have been usedin wound management and bone healing. For example, prior irradiancebased technologies are typically high-irradiance systems that arerelatively expensive, require a specialized medical facility and staffto operate and maintain, and require patients to make frequent trips totheir clinic to receive a light-based treatment. Current standardmethods of high-irradiance systems provide treatment light doses overshort durations ranging from 60 seconds to 30 minutes using high-poweredlasers or lamps, which emit high-irradiance light from 50 mW/cm² to 1000mW/cm². One significant advantage of certain devices and methodsdescribed herein is the avoidance of high-irradiance light sources andthe ability to deliver energy at a low irradiance (within the range ofmicrowatts to milliwatts per square centimeter [μW/cm², mW/cm²], withprecision dosimetry (uniform light across a treatment surface area). Inorder to deliver the same total fluence as high-irradiance systems, thelow-irradiance delivery device can remain in contact with the wound bedcontinuously for extended periods of time. Devices and methods describedherein include a flexible light-emitting bandage or element that ishighly-conformable to body contours and provides extended periods ofillumination as a wearable, battery-powered device. The device can befabricated as a bandage, cast, or brace, or be embedded within aprosthesis to decontaminate wounds, treat localized infected ulcers, andstimulate wound healing.

In an embodiment a wearable medical device is provided that can delivertherapy to skin wounds continuously and/or intermittently for days at atime using low irradiance. In embodiments the device has the ability tokill bacteria including multidrug resistant organisms (MDROs) withoutthe use of antibiotics.

The first series of procedures conducted to validate the antimicrobialcapabilities of the LIMB system were designed to determine if priorliterature on visible blue biostimulation dosing for sterilizationadministered over acute periods (seconds to minutes at 40-100 mW/cm²)would effectively translate to a low-irradiance (up to 24 hours at0.2-10 mW/cm²) delivery method that could still achieve a minimum 2.0log (99.0%) bacterial load reduction. Validation was conducted in twoseparate phases. Within Phase 1, the antimicrobial properties of theLIMB system were first evaluated on clinical isolates ofmethicillin-resistant Staphylococcus aureus (MRSA) by subjecting eachculture to identical fluences of light (75 J/cm²), but the totalirradiance (mW/cm²) and time of delivery were altered. Following thisperiod, the LIMB system was evaluated at varying irradiances deliveredcontinuously over 24 hours to determine if there was a minimumirradiance at which a >99.0% bacterial load reduction could still beachieved.

Devices and methods described herein inhibit the colonization of MDROsto form biofilms in acute and chronic wounds.

The inhibition of colonization of MDROs and the effect on the formationof microbial biofilms is evaluated in Example 2.

Devices and methods described herein have the ability to reduce andeliminate biofilms that have already formed in wounds.

Effects on P. aeruginosa biofilms are evaluated in Example 3.

In an embodiment a device disclosed herein can physically disrupt theintegrity of MDRO biofilms, and subsequently allow for antimicrobialsand disinfectants to penetrate through the biofilm. In doing so, thedevice can provide an additive and/or synergistic antimicrobial effectwhen used in conjunction with other pharmacological agents.

Due to evidence which documents the role of biofilms and their enhancedvirulence factors, particularly due to their nearly-1,000-fold increasein tolerance of antibiotics, disinfectants, and antiseptics whencompared to their planktonic counterparts, the potential of usingadjuvant pharmacological agents in conjunction to the LIMB system as anantimicrobial combination therapy was evaluated. Further evaluation ofthe effect on biofilms is provided in Example 4.

By affecting the bacterial cellular machinery the energy admitted fromthe device can inactivate plasmids and small molecules that conferbacterial resistance to specific forms of antibiotics. For example, byusing the device on a chronic wound that is infected with MRSA, thedevice renders the bacteria sensitive to penicillin-type antibiotics,thus enabling methicillin and other early generation penicillin drugs toeffectively kill the bacteria.

Light Sources

Current illumination systems for phototherapy (photorejuvenation,actinic keratosis, psoriasis, photodynamic therapy, etc.) typicallyrequire removal of bandages and dressings to provide the therapy underfixed illumination systems. The typical light output of these systems(once contacting the skin surface) is >10 mW/cm² and are usuallydelivered at high irradiances (mW/cm²) over 5-30 minutes.

As they pertain to phototherapy, and specifically wound care, prior artdevices and methods disclosed herein DO place undue temporal and spatiallimits on the duration of therapy. In embodiments of devices and methodsdescribed herein, subjects do not need to travel to, and have thetherapy conducted in, a hospital or other facility.

Devices and methods described herein avoid, from a biologicalperspective, shortcomings of fixed phototherapy illumination units whichcan have negative side effects on wound treatment. Exposing the patientwounds on a frequent basis opens the wound to potential pathogeninvolvement, inducing greater risk of infection. Additionally, althoughinitial light exposure may cause the cell death of some bacteria, thebiggest issue is that once treatment is complete, the bacteria andpathogen are back to growing, replicating every 20 minutes. Hence,although an infection or wound may have a beneficial impact fromphototherapy for the duration of therapy (during light delivery), theinfection or wound healing process can be impaired immediately afterinitial treatment, thereby effectively making the treatmentinconsequential.

The following is a list of prior art in the field of light deliveryproducts and technologies for medical products, specifically forphototherapy and for wound care.

Direct and Focused Illumination Systems

In the medical device field there are numerous methods to deliver lightto perform a medical procedure, but the two most common methods aredirect and focused illumination. Direct illumination occurs with a bareor diffused light source placed a distance of several centimeters tometers from the patient. Direct illumination devices are rarely attachedto the patient. In general, the patient is required to positionthemselves to the illumination source. Examples of light deliverydevices that fall within this category include conventional phototherapyunits, such as the standard light box (and hand/foot unit) that emitUV-A, UV-B or narrow-band UV-B light. Phototherapy units are usedprimarily for the treatment of inflammatory skin diseases such aspsoriasis. The units are also used in conjunction with orally ortopically administered psoralens that photoactivate with UV-A light inthe treatment of severe psoriasis and extensive vitilligo. Thistreatment is known as PUVA (psoralen UV-A) therapy. For systemicdiseases such as cutaneous lymphoma, graft versus host disease, andsystemic sclerosis, extracorporeal photophoresis is performed where thepatient ingests the psoralen and the blood is exposed to the UV-A lightoutside the body and then re-infused into the patient. The DUSA (bluevisible light) and Galderma-Metvix (red visible light) systems are usedfor the treatment of actinic keratoses (pre-malignant skin growths) andsuperficial basal cell carcinomas. They work via topical aminolevulinicacid (DUSA) and methyl-aminolevulinic acid PDT.

Focused illumination, both internal and external to the patienttreatment site, requires illumination that has an optical system todirect light from the illumination device to specific areas onto thepatient, typically in a controlled beam shape and beam intensity. Inmany cases the optical system is composed of one or more optical fibersthat use total internal reflection to collect light at one end of thefiber, transmit the light, and exit with a specific numeric aperture atthe other end. Typically, this approach requires larger fibers or anarray of large fibers to illuminate large areas (>5 mm). Illuminatingmore than a single fiber requires sophisticated coupling of the lightinto the fibers. This coupling is usually inefficient and can have verylow coupling efficiency (<10% efficiency). Similar to directillumination, the focused illumination approaches are rarely done inwhich a patient wears a device.

For FDA-approved Photodynamic Therapy (PDT) indications, there arenumerous light illumination devices meeting the direct and focusedillumination schemes. For example, for Barrett's esophageal cancertreated with PDT, a focused illumination system is implemented using afiber optic cable attached to an FDA-approved laser system such as theAngio Dynamics PDT 630 nm laser. Alternatively, a direct illuminationapproach to PDT for actinic keratosis is done using similar devices suchas DUSA's Blue-Light Phototherapy Lamp or Galderma's Aktilite which isalso used for basal cell carcinoma skin cancer.

There are also a few direct and focused illumination devicesspecifically used in wound care healing using light. For example, thereis the Biolight BCD 650. The device is hand-held and is only suggestedfor light delivery over several minutes.

Portable and Wearable Illumination Systems

As can be seen from the examples and from existing illumination devices,many are not portable (for example, because they are difficult tophysically move), and in general this means the illumination devicecannot be worn or used by the patient during Activities of Daily Living(ADLs). In some embodiments, devices disclosed herein are portable andwearable.

Devices

Embodiments of the device include a light-emitting bandage or elementfor the delivery of 405 nm (+/−10 nm) light at low irradiance (<10mW/cm²) over a 24-72 hr period. In one embodiment, the system isconfigured to include a wound dressing and a power pack.

Wound Dressing

In one embodiment, the wound dressing includes:

-   -   1. a wound surface contact layer (in embodiments it is        hydrophobic and can, for example: protect the patient from the        internal circuitry of the dressing; in embodiments it is        hydrophilic and can, for example, collect exudate from the        wound),    -   2. a rigid-flex circuit layer which is constructed in a        gapped-hexagon pattern for even distribution of light and        flexibility to conform to body surfaces of a wound, and    -   3. a backing layer which, with the wound surface contact layer,        (in embodiments it is hydrophobic, and can for example, form a        seal protecting and enclosing the circuitry within) encloses the        circuitry within.

In and embodiment the wound dressing is 5 cm×30 cm and includes a layoutillustrated in FIGS. 1A and 1B. FIG. 1A illustrates a normal to top viewof a device 100 having a single segment without foam. FIG. 1Billustrates an angled top view of the device 100 having a single segmentwithout foam. Over each hexagon area on the PCB (composed of a whitereflective PET or polyimide) illustrated in FIGS. 1A and 1B, resides ahexagon light guide (22.5 mm in the largest diagonal, 11.25 mm along anedge).

For example, FIG. 2 illustrates a side view of a hexagon light guide andelectronics layout 200. FIG. 3 illustrates a top view of the hexagonlight guide and electronics layout 200. The hexagon light guide andelectronics layout 200 includes hexagon light guides 202.

The hexagon light guides 202 illustrated in FIGS. 2 and 3 are composedof a 0.5 mm medical grade PMMA (Evonik PMMA L119673/21/1 0.5 mm thickmaterial). On the bottom surface of the hexagon light guides 202, thesurface is flat. On the top, a pattern of micro-dots 204 is layered toevenly (uniformly) illuminate the entire light guide surface. Thepattern accounts not only for side-emitting LEDs which illuminate thehexagon but accounts for other light diffusion surfaces that provideuniformity including a diffuser (if needed) and thehydrophobic/hydrophilic foams described above. FIG. 2 has an internalreflective surface feature label which represents the pattern ofmicro-dots and other diffusion surfaces.

A reflective PET layer 206 (which could be combined with other diffuser,prismatic, or polarizing materials) is used as a means to create aneffect of total internal reflection (TIR), which allows the lightemitted by side-emitting LEDs 208 respectively attached to a side ofeach of the hexagon light guides 202 to internally reflect light fromone side of the respective hexagon light guide 202 to the other side.

The reflective PET layer 206 has a higher index of refraction than thematerial of each hexagon light guide 202 and the side-emitting lightentrance of a given hexagon edge allows “most” of the light to go from alow index of refraction environment (for example, air) into the hexagonmaterial above the critical angle needed for TIR. The spacing of themicro-dots 204 on the top (the light emission surface facing thetreatment site) or bottom of the light guide creates a mechanism for thelight that is undergoing TIR to bounce out of the hexagon light emissionside because the light angle changes enough to meet the boundarycondition for refraction (out of the hexagon light guide surface) ratherthan reflection and continuing via TIR down the remainder of each of thehexagon light guides 202. The spacing of the micro-dots 204 is generatedto make sure that light leaks (breaks the boundary condition) uniformityacross the hexagon light emission surface.

In certain embodiments, a micro-array pattern of micro-dots can beplaced on the bottom of the hexagon (facing the reflective white PET,residing below the non-light emission surface side of the hexagon), togenerate uniform light emission from the top of the hexagon towards thetreatment site. However, when one presses down on the hexagon lightguides 202, a hot spot is created, because the design assumes there is asmall air-gap between the light guide micro-dots 204 and the PET 206.When the unit is pressed upon the air gap disappears and more lightexits the hexagon light guides 202 where there is no air gap. To avoidthis problem, the micro-dot was placed on the top of the hexagon lightguides 202—facing the PET 206/diffuser. This approach or micro-dotpattern assumes the air gap is completely removed.

In certain embodiments, foams with adhesive coatings on top of thelight-emitting surface of the light guide can cause light to bounce outof the light guide closest to the LED input in the light guide. Asuitable micro-dot pattern to avoid the light existence from theadhesive has not been successfully developed. The adhesive generates anoptical environment that reduces TIR a short distance from the LEDinput. The current solution is to apply foams, diffusers, polarizers,etc. without any adhesive that may make contact with the light guidelight-emitting surface. However, adhesive on the foam, diffuser, andpolarizer on the side opposite of the light guide contact side ispermissible and can work with a given micro-dot pattern. The adhesivecould consist of an acrylic adhesive, silicon adhesive, or askin-friendly or trauma-friendly adhesive.

To get light into the hexagon light guides, the primary mechanism is touse side-emitting LEDs from TechLED (Marubeni). The side-emitting LEDscommonly used for wound care applications emit 405 nm light. In certainembodiments, three edges illuminate the hexagon, as illustrated in FIG.4. FIG. 4 illustrates a view of side-emitting LED 400 placement. Giventhe size of the current hexagon, three side-emitting LEDs can reside oneach of the three edges (total of nine side-emitting LEDs per hexagon).In future versions, for a given edge, each LED in the array could emitdifferent wavelengths for different wound healing therapeutic purposes.

The backing layer composed of a foam can have adhesive on either side,as discussed below with respect to FIG. 2. This adhesive layer wouldallow the PCB components (but not the light emission surfaces of anylight guide) to stick to the foam backing. It would also allow foam(without any adhesive) which is on top of the light-emitting surface ofthe light guide to seal to the backing layer. The backing layer couldcontain other foam, diffusers, polarizers, or optical materials(transparent, semi-transparent, or opaque).

The PCB components, such as the LED drivers, LEDs, and other parts canbe domed with epoxy to make the parts/circuits water proof. Thefollowing PCB can include thermistors to monitor temperature within thewound dressing. Data from the thermistors can be sent back to the powerpack by a connector cable.

In an embodiment, a plurality, for example, three, of these wounddressings can be connected to one another and receive power from thepower pack by the connector cable. Hence the units are stackable andmodular. Multiple dressings (or zones) can be powered through a singleconnector which goes to the power pack. Multiple data lines from a givendressing can traverse through multiple dressings so as to only requireone location to acquire the data rather than multiple ports perdressing.

Table 7 provides a description of an embodiment of a hexagon light guideand electronics layout according to one implementation. For example, theproperties described in Table 7 may illustrate properties of anembodiment of the hexagon light guide and electronics layout 200.

TABLE 7 Example hexagon light guide and electronics layout description.LIGHT GUIDE Type Side-emitting illumination source, e.g., a LightEmitting Diode (LED) Shape Polygonal, e.g., hexagon Size 5 mm to 50 mmin the longest dimension; e.g., 20 mm Thickness 0.100 mm to 1 mm; e.g.,0.500 mm Bottom Surface In contact with PET white reflective material(facing PCB) Top Surface (facing Composed of microstructures,microlenses, microdots to direct light treatment site/skin) out of thelight guide based on total internal reflection Microstructure FeaturesTypically under several hundred microns, <100 um Microstructure ArrayTypically non-uniform to allow light to exit equally across the entiresurface. Lower density (fewer microstructures) near the side- emittingillumination source. Higher density (more microstructures) near thecenter of the polygonal shape. Pattern can be linear, or two-dimensional, where two-dimensional patterns typically assume side-emission from multiple input faces and the microstructure pattern emitsfrom each side of illumination to the center of the polygon. PCB ShapePolygonal, e.g., hexagon with extra width where LEDs are placed Size 5mm to 50 mm in the longest dimension; e.g., 20 mm Thickness 0.125 mm to1.6 mm; e.g., 0.8 mm Material of PCB FR-4 LED Location Attached to PCB(defined above) Type Side-Emitting Size (Footprint) 2.10 mm width, 0.6mm height, 1.0 mm length (from lens to back) Size (Lens) 1.70 mm width,0.6 mm height, 0.5 mm length Lens/Optic FOV +/−82 Degrees X-Dim(Horizontal) Lens/Optic FOV +/−67 Degrees Y-Dim (Vertical) RadiatedPower 20 mW LED ARRAYS LEDs in an Array LED Array could be composed of asingle LED or multiple LEDs. Number of LEDs on any given side of ahexagon that is 20 mm will be up to 3 LEDs. Spacing between LEDs can belinear or non-linear (linear preferred). Location of array along oneside of a hexagon can be symmetric or non-symmetric from center(symmetrically located preferred). Array Location If one side, assume alinear microstructure light guide. In most cases, assume two-dimensionalmicrostructure and LEDs on more than one side of hexagon. Assume anarray on three-opposite sides with one wavelength. All six sides of thehexagon could have an LED array. Each side could have the samewavelength LED. 3- opposite sides of the hexagon could have onewavelength while the other 3-opposite sides of the hexagon could haveanother wavelength. For example, 3-opposite sides of the hexagon couldhave an LED array that emits 405 nm light and the other 3-opposite sidesof the hexagon could have an LED array that emits 680 nm light. LEDArray A single array on any given side of a hexagon could include moreWavelengths than one wavelength. For example, within one array, assume 3LEDs in the array, could include two 680 nm emitting LEDs and a single850 nm LED. LED Control Each LED could be individually controlled. EachLED array could be individually controlled (preferred for multiplewavelength variations), or all LEDs on a single PCB could be controlled(preferred for single wavelength, this is the current process) OTHERMATERIALS PET Reflective, white material laid down on PCB between theLEDs/arrays Conformal Coating Over electronics and LEDs (but not lenses)to protect parts Adhesive Zones On PCB to lay down PET and otherfloating materials Thermally Conductive Manage heat transfer from LEDsand PCB away from skin and out Heatsink Materials of bandage. Thermallyconductive materials include copper, aluminum, other. Surface area keyelement in reducing heat. Magnets may be used as a mechanism to transferheat. Outer Dressing: Patient-contacting side/skin-side material may beoptically clear to Silicones (Treatment maximize light throughput whileminimizing light output of LED Side) and reducing thermal waste fromeach LED. Thickness 1 to 2 mm. Outer Dressing: In some embodiments, itmay be preferable to have a silicone with Silicones (Air Side) some heattransfer capability. NuSil provides (a silicone material (MED15-2980Pand MED20-2955P) that is thermally conductive. Air side silicone can beopaque, which can aid in reducing any light projecting towardspatient/outside observer's visual field. Inner Dressing: Silicone withlow durometer (<50) with diffusant. This layer Silicone (Interstitial)diffuses the LED point source light such that the irradiance measuredover the LED is similar to that over the remainder of the hexagon lightguide. This layer also acts as a mechanical fixture to keep the hexagonlight guide in place in relationship to the LEDs and LED arrays.Silicone over Foam Silicone may be implemented as a surface because itcan be Outer Dressing or optically clear, non-adherent, and can becleaned easily between Equivalent daily uses. It is also very flexiblewhen it has a durometer between 10 Shore A to 60 Shore A (18-30 Shore Apreferable). Also, by encapsulating opto-electronics, the silicone canbe ripped off after use and repackaged and re-sterilized to takeadvantage of the long shelf-life of the opto-electronic parts. Utilizingall silicone parts for the outer dressing along with inner dressingmakes it easier/simpler to adhere these materials together with siliconeadhesives or with over-molding. Adhesive Zones on For burn wounds, noadhesive desired to avoid pulling at tissue that Outer Dressing may behealing. For chronic ulcers, like diabetic foot ulcers, potentiallydesirable to have adhesive. Other Layers Other layers may include foams(hydrophobic or hydrophilic), polyurethanes, or other medical gradematerials that are flexible, durable, light-transmitting (patientcontact side), and can aid in fluid management. Preferred fluid For burnwounds, silicone encapsulated bandage sits over the top of management ahydrogel placed in wound (for example, a hydrogel from Advanced MedicalSolutions, Ltd). Hydrogel can be used on dry- wounds. Forlow-medium-high exudating wounds, optimal dressing in the wound forfluid management is a calcium alginate (for example, a calcium alginatefrom Advanced Medical Solutions, Ltd), wetted or wet from exudate.HEXAGON SYSTEM Single Hexagon Layers Primarily composed of PCB, PET,light guide, LED, localized wire (Locally) management system, localizedinterstitial silicone layer, localized silicone patient contacting side,localized thermally conductive material(s), localized thermallyconductive silicone Hexagon Layers All of the above but full siliconelayers, wire management, and (Device) thermal conductive layers expandedaround all hexagons. Primary Hexagon Light 3 × 6 array, lilypad (centerhexagon surrounded by 6 outside Patch Arrays in Use hexagons). StackingInstead of larger array sizes, there is the option of stacking thesmallest site arrays (i.e. the 3 × 6 array and lilypad) Ideal HexagonSize 20 mm in longest dimension. Optimal range 5 mm to 30 mm in longestdimension. Ideal Hexagon Array 3 × 6 array, lilypad (for example, FIG.9), and large blanket Sizes (3 ft. × 3 ft. or 1 m × 1 m) Large BlanketSizes 50 × 50 hexagon array or an array of stacked 3 × 6 arrays orstacked lilypads Ideal Hexagon Array 3 × 6 array, lilypad (for example,FIG. 9) Size for 5%-to-15% TBSA Burn Ideal Hexagon Array Large blanket(3 ft. × 3 ft. or 1 m × 1 m) Size for >15% TBSA Ideal Hexagon Size for 3× 6 array, lilypad Chronic Ulcers (Diabetic Foot and Pressure Ulcers)Array of Hexagon 1 × 1, 3 × 3, 3 × 6, 6 × 6, 3 × 12, 12 × 12, 25 × 25,Range (when Hexagon 50 × 50; specifically 3 × 3, 3 × 6, and 50 × 50Diagonal = 20 mm) Hexagon Size Range 5 mm, 10 mm, 15 mm, 20 mm, 25 mm,30 mm, 35 mm, 40 mm, 45 mm, (Based on Diagonal) 50 mm; specifically 20mm for flexibility around arm, wrist, leg. 5 mm ideal for smallerextremities like fingers. 50 mm ideal for large flat surfaces likechest, back, or thigh. HEXAGON ARRAY SPACING Spacing Between Balancebetween spacing, flexibility, and light coverage. Preferred Hexagons gapbetween hexagons is between 0.5 mm to 3.00 mm, with an ideal distance of1.5 mm to 2.00 mm. Problem of small air When bending hexagons overlapand crash into near neighbors. gap Problem of large air Light uniformitydecreases. gap WAVELENGTH AND IRRADIANCE Wavelength Range 380 nm-430 nm;for example, 405 nm plus/minus 10 nm. Other ranges (Wavelength 1) ofinterest 425 nm plus/minus 10 nm and 470 nm plus/minus 10 nm. WavelengthRange 650 nm-700 nm; for example, 675 nm plus/minus 10 nm. Other ranges(Wavelength 2) of interest 625 nm plus/minus 15 nm and 690 nm plus/minus15 nm Wavelength Range 830 nm plus/minus 20 nm. Other wavelengths ofinterest 810 nm (Wavelength 3) plus/minus 20 nm and 850 nm plus/minus 20nm. Wavelength 1 1 mW/cm2 to 10 mW/cm2; for example, 3 mW/cm2 IrradianceRange Wavelength 2 0.3 mW/cm2 to 2 mW/cm2; for example, 0.75 mW/cm2Irradiance Range Wavelength 3 0.3 mW/cm2 to 2 mW/cm2; for example, 0.75mW/cm2 Irradiance Range DURATION OF TREATMENT/WAVELENGTH Duration ofTreatment 24 hours continuously or pulsed. Wavelength 1 Pulsed Treatment5 min. on/off, repeat up to 24 hours. If pulsed, vary irradiance by 2xWavelength 1 the irradiance of the continuous treatment. In oneembodiment, range of pulsing 5 min. on/off up to 30 min. on/off.Asynchronous pulsing is an option (i.e. 10 min. on/5 min. off, repeat).Duration of Treatment Greater than 6 hours of continuously or pulsedtreatment. 12 hours Wavelength 2 and 3 to 24 hours ideal. Combination of6 hrs. continuously of wavelength 1 followed by 18 hours of Wavelengths1 and 2; 1 wavelength 2 or 3 or a combination of wavelengths 2 and 3.and 3; and 1, 2, and 3 Alternatively, wavelengths 1, 2, and/or 3 runsimultaneously up to 24 hours. PULSE WIDTH MODULATION Wavelength 1 PWMPulse Width Modulation (PWM) is used to tune the irradiance level byturning on and off the illumination at 10 to 100 Hz (Tyler range).Wavelength 1 will have a PWM of 25% to 75%. PWM Waveform TypeSynchronous and asynchronous PWM Waveform Square wave PatternWavelengths 2 and 3 Low PWM value to account to lower irradiancerequirement. PWM Thermal Management Vary PWM to control thermaltemperature Visual Perception During off-time during treatment cycle, tohelp aid people in realizing the device is still on and running, one canset the PWM in the 1%-to-10% range rather than 0% and then raise the PWMback to peak value when the treatment cycle is supposed to be on.SENSORS General Description Device has sensors that relay informationregarding the wound to the power-pack or via wireless communication to acomputer POWER PACK General Description Device is controlled and poweredby a wearable lightweight power- pack that can run off battery or walloutlet and controls the LEDs USE-CASE Example 1 Device is placeddirectly on the surface of the skin, skin orifice, endothelial orepithelial surface, skin wound or implanted within the body or onto animplantable medical device (e.g., prosthesis) Example 2 Can be left incontact with the patient continuously for up to 7 days

In at least one embodiment of light patches disclosed herein, light isgenerated by LEDs. LEDs may generate heat, which may raise thetemperature of the light patch. In some embodiments, it may bedisadvantageous for the light patch to be raised to above 41° C. at arequired light dose. The LEDs may be pulsed using Pulse Width Modulation(PWM) to modify a total irradiance of the patch, and to reduce the totalheat that is generated by the light patch.

A material of the light patch and of an associated PCB may be selectedto reduce a temperature of the bandage. For example, a first design maybe directed towards thermal dissipation with two, four, and six-layerboards using standard FR-4 and loz/ft of copper. A second design mayinclude a four-layer, 2 oz copper board. A third design may includealternatives to FR-4 including, for example, a metal core.

Other thermal management techniques may include changing the layerssurrounding the light patch opto-electronics (for example, layersencapsulating the LEDs) by considering: adding moresilicone/polyurethane to a patient side of the light patch to increasethe temperature barrier; using optically clear materials to reduce LEDpower requirements; adding heat sinking materials to the back of eachhexagon PCB; or pulsing a certain number of hexagons at any one instant,faster than the human eye can see.

The optics around the light patch may be optimized to be delivered usinghexagonal light guides with LEDs on 3 edges; where each light guide andLED array is situated on a rigid PCB that is also hexagon-shaped. Toallow the system to bend, all the flexing may occur between the hexagonPCB islands. Rigid flex circuits may be used for connecting the PCBislands, but traditional rigid flex boards may not allow for enoughflexibility in the small space allowed between hexagons, which may bebetween approximately 1.3 to 2.0 mm. As an alternative, thin (28 gauge)wire may be used to connect multiple hexagons together. For example,FIG. 34 illustrates a top view of multiple hexagons 3400 connected bythin wire.

The layout of FIG. 34 may be problematic from a manufacturingperspective and may have reliability issues in regard to stress onsolder joints, particularly if the Hexagon PCB islands are flexed oftenand/or with extreme bending forces. Accordingly, one of at least threesolutions may be implemented according to the foregoing disadvantages.

In a first solution, flat flexible cables may be used. For example,surface mount or through-hole flat cable jumpers may be used to connectthe array of hexagons together. FIG. 35 illustrates a top view of a flatflexible cable 3500 according to an embodiment. FIG. 36 illustrates atop perspective view of another flat flexible cable 3600 according to anembodiment. In the embodiments illustrated by FIGS. 35 and 36, eithersurface mount or through hole connectors styles could be used such thatthe connections between hexagon PCBs could be made while still in thepanel or at any more efficient stage in the PCB fabrication/assemblyprocess.

In a second solution, a conductive material may be adhered to each ofthe hexagon PCB s for electrical connections. For example, conductiveink may be printed onto a plastic sheet or a copper foil with a Kaptonbacking to be used for the electrical connection. The hexagon PCBs arestill rigid PCBs but are connected by—ideally one—flexible circuit. FIG.37 illustrates a layout of a back plane connection layout 3700 accordingto an embodiment. FIG. 38 illustrates a layout of a back planeconnection layout 3800 according to another embodiment.

In a third solution, a ZIF style connector may be used to connect eachhexagon to one flat flex circuit. The flexible PCB may designed toconnect all the hexagon PCBs in the 3×6 array together in a simplerprocess than soldering multiple connections. For example, FIG. 39illustrates shows a layout design for a flat flexible circuit 3900according to an embodiment. The arrows show the direction andapproximate location of the connector located on each of the hexagonPCBs in this potential arrangement of connectors. The half hexagon willcontain the connection out to the power source. The flat flexiblecircuit could be made to most easily be fit into place, reducing thenumber of individual hexagon-to-hexagon connections to be made.

Power Pack

In an embodiment a device comprises a power pack. In an embodiment thepower pack is comprised of the following:

-   -   Rechargeable Battery    -   PCB control module    -   Power/Data Cable    -   Separate Power Recharge Station for Depleted Batteries

The rechargeable battery can be inserted and removed from thestructure/housing of the power pack. When fully charged, the batterywill last up to 8-24 hours. Upon charge depletion, a new fully chargedbattery needs to be inserted to continue therapy. The depleted batterywill need to be recharged on the separate power recharge station.

In an embodiment:

-   -   The power pack is configured to receive power from a wall        outlet.    -   The power pack is configured to provide warning indicators using        LEDs, sound, and/or displays.    -   The power pack is configured to allow data from the wound        dressing to be processed and analyzed in the power pack.    -   The power pack could send data to a wireless server or network        to record data and take in instructions or regiment information        to individualize treatment.

Array

Embodiments of the present disclosure further include varying the sizeand shape of each light module, as well as the spacing between adjacentlight modules.

Embodiments of the device include a light patch that is designed andbuilt out of fiber optics. The fiber optics are in a bundle at one endwhich receives light from an LED source and then the light undergoes TIRthrough the fiber up to the other end. At the other end the fiber opticsfan out into a flat array as shown in FIG. 5. FIG. 5 illustrates a fiberoptic light guide 500, used for photodynamic therapy applications, wherered lines indicate fiber optics and where each of the fiber optics is0.5 mm in diameter. The fiber optic channels in the flat array zone areetched in a way to allow light to exit the TIR condition and refract outof the fiber optics. The etch is optimized to create a uniform lightleakage over a 10 cm×10 cm area.

This design is very flexible and efficient, particularly when the deviceis bent causing “tipping” (generating a bend with a radius of curvaturein one-dimension). The reason the device is flexible is because thelight guides are not a “single body” so they allow tipping and some“tilting.” Tilting is a bend in the device where the bend has a radiusof curvature in one-dimension; typically orthogonal to the tippingbending direction. The light delivery and uniformity is efficientbecause the light is already in the body of a given light guide channelor fiber optic channel if there is any bending (or tipping).

Due to manufacturing complexities with fiber optics, embodiments includea bandage that utilizes a “single body” light guide as shown in FIG.6(a). FIG. 6(a) illustrates a solid body light guide design 600 foreven-illumination phototherapy applications. FIG. 6(b) illustrates anexample implementation 602 of the solid body light guide design 600according to an embodiment. FIG. 6(c) illustrates a power pack 604corresponding to the example implementation of the solid body lightguide design 600 according to an embodiment.

Instead of discrete light guide channels like fiber optics the lightguiding activity occurs in a single device (plate) which receives lightfrom multiple and overlapping light sources (for example LEDs). Thesingle body light guide design 600 is 0.5 mm and can receive light fromside emitting LEDs in an array attached to a flexible PCB, wherein thered arrows illustrated in FIG. 6(a) indicate light rays from the LEDs.This design is easier to produce and it does allow forbending/flexibility for high radius of curvatures such as the chest wall(typically after mastectomy for a woman who has cutaneous metastases ofbreast cancer). The design also allows for more uniform and repeatableuniformity across the light guide surface. However, this design is notvery flexible because now the light guide (compared to fiber opticchannels separated from one another like in FIG. 5) is a single body soit retains rigidity despite the initial flexibility of the 0.5 mm thickmaterial. Additionally, light may NOT be in the body of the light guidechannel if there is any tipping (particularly extreme tipping).

As an alternative to the fiber optic system or the single body lightbody approach, embodiments of the device further include an LED arrayallowing flexibility in not only one dimension but in both the verticaland horizontal direction. For example, FIG. 7(a) illustrates a top viewof an LED array 700 approach to flexible light delivery. FIG. 7(b)illustrates a side view of the LED array 700 approach to flexible lightdelivery.

In embodiments the devices described here have improved flexibility overfiber optic channels, and are configured to optimize evenness ofillumination, for example, from an LED array which might otherwise haveissues with even illumination due to the divergence of the light fromthe top emitting LED. Another problem causing a lack of uniformity isthe inability to diverge and homogenize the light in such a short throwdistance from the LED to the skin (it is several millimeters).

With fiber optics (FIG. 5) the device embodies flexibility (primarily inone dimension) but low light uniformity and is difficult to manufacture.With the single body light guide (FIG. 6[a]) the device is configured tohave light uniformity but limited flexibility in both dimensions but thedevice is much easier to manufacture. With a discrete LED (light) system(FIGS. 7A and 7B) the design achieves two-dimensional flexibility andmanufacturing is fairly easy, but uniformity can be compromised.

In embodiments the devices disclosed herein provide discrete lightemission channels with at least two-dimensional flexibility and have thecapability of emitting uniform light over a low profile (smallthickness) in conjunction with ease of manufacturing.

One approach is to design the single body light guide to act as thefiber optic channels by breaking the single body light guide into anarray of smaller single body light guides as shown in FIG. 8. FIG. 8illustrates discrete light guides 800.

With the design in FIG. 8, the approach creates “pivot points” fortipping. Tilting is still limited. Compared to a single body lightguide, this design approach reduces having light already in the lightguide at the pivot points. The main drawbacks to this approach are thatprimarily only one axis has increased flexibility and, since the lightis diverging, as indicated by the red lines in

FIG. 8, there may be a decrease in the irradiance at the top of eachlight guide channel, particularly if the length of the channel is long,for example, over 50 mm.

An alternative approach to long/elongated but smaller single body lightguides is to develop small but multi-faceted shapes that allow light toenter the light guide from multiple inputs to create uniformity whilealso creating a functional shape that allows for multiple deflection ormultiple dimensions of flexibility. An optimized shape that meets thesecriteria includes hexagons as shown in FIG. 9. FIG. 9 illustrates ahexagon design 900. This design also addresses the light divergenceproblem of long light guides and avoids the excessive throwdistance/height of an LED array needed to get uniform coverage.

In FIG. 9, each hexagon is isolated, tied by a thin flex circuit.Flexibility is enabled on six planes, and each hexagon has a single LED.Each hexagon provides even illumination, which eliminates the diffusionproblem of the LED array, and the hexagon surface area improves thelight divergence issue.

Other polygon shapes can be used. For example, FIG. 10 illustrates anoctagon design 1000. However, the hexagon shape is desirable because itallows for a wide degree of flexibility across multiple pivot points butwithout sacrificing continuous illumination between the spaces (aka“dead zones”) between each discrete light guide. As can be seen in FIG.10, there are much larger dead zones between each light guide, such thatthere will be a much larger effect of light falloff from light guide tolight guide and the area in the dead zone will be dimmer/darker comparedto the light exiting a given light guide. The dead zone and brightnesseffects can be minimized with a hexagon-shaped array compared to someother polygon shapes. Other shapes like triangles and squares could begood light guide shapes but with triangles, light uniformity frommultiple edges could be a problem and an array of closely stackedsquares (or rectangles) will have to deal with a greater number ofissues pertaining to dead zones, light uniformity, and potentialbuckling when the array is bent.

In one embodiment, a preferred size is of importance based onflexibility required, the light output (expressed in milliWatts [mW]) ofthe LED, and the light input required for a therapeutic response.Assuming that a pivot point is based on the longest diagonal of ahexagon, then the size (or diagonal) of the hexagon should be set sothat the smallest hexagon can pivot around the smallest-sized anatomyrequired for treatment. If a finger is to be treated with light, forexample, then an ideal size for a hexagon light guide is 10 to 15 mmalong the diagonal. For a leg or torso, the hexagon size could belarger, such as approximately 50 mm.

A tradeoff on the hexagon size is that smaller hexagons require moreLEDs if the hexagons are built into an array that will cover a largersurface body area. As the hexagon size gets larger, the LED requirementsalso increase—depending on the irradiance required. If the light outputout of the light guides needs to be above 1 mW/cm², then the LED has tohave a large output, when coupled as an LED array, to achieve theirradiance over a large throw (light divergence) distance. Essentially,there comes a point where a large hexagon becomes as big as, orfunctions just like, the single body light guide as discussed in FIG.6(a).

For arms and legs, a preferable hexagon size is between 15 mm to 25 mmwith 20 mm and 22.5 mm as a most preferable size. For fingers, nose, orear anatomy, a hexagon size of 10 mm to 15 mm is most preferable. Forlarger anatomical surfaces, 35 mm is preferably the maximum hexagonsize.

The gap between hexagons or each individual polygon is important. Thegap provides the pivot points and flexibility. The gap also provides theareas where the individual light guides and circuitry are connected andwhere some hard-mounted circuits such as the LEDs, resistors, LEDdrivers, and other items, sit. In embodiments an optimized gap allowsfor flexibility and placement of electronics while at the same timeminimizing dead zones (areas where light is not present and where lightis uniform from one polygonal light guide or emission surface to thenext) and making sure that, as the entire electro-optical system isbent, the individual light guides do not crash into each other. For thehexagon, an exemplary gap size is between 0.75 mm and 2.50 mm forhexagon sizes ranging from 15 mm to 25 mm, respectively. For hexagonsthat are sized 22.5 mm, an exemplary gap is approximately 1.6 mm. Ingeneral, the preferable gap to diagonal width of a hexagon, aspertaining to a percentage, is between 5% and 10%.

As for the layers connecting the individual hexagon light guides, thereare, in embodiments, one or more polyimide layers that includeelectrical traces and positional features to solder LEDs, resistors,pulse-width-modulators, LED drivers, MOSFETs, amplifiers, and otherbasic electrical components. In embodiments, the layers are between 25μm to 500 μm thick and although the layers are thin between the hexagonlight guides, there is a more rigid (thicker) layer behind the lightguides and where the LEDs sit so as to provide greater reliability tothe core light-emitting objects even when the connection layers arebeing flexed.

In embodiments, connections between the individual hexagon light guidescan be flat bridges or could be multiple flex connections. For example,FIG. 11 flat connections 1100 between light guides of an LED and lightguide array, and FIG. 12 illustrates multiple flex connections 1200between components of an LED and light guide array. Additional sensors(temperature sensors, pH sensors, capacitance sensors, etc.), can bedispersed around the primary connections between the individual lightguides.

Pulsing

Killing organisms requires light, a photosensitizer, and oxygen.Administration of the light at higher irradiance depletes the endogenousphotosensitizer and O₂. In some settings, such as in hypoxic wounds, thelight can be pulsed with 2 to 10 minute dark periods to allow theorganisms to produce photosensitizer and restore the tissue oxygentension. The dark periods may need to be longer for certain parasites,such as roundworms and flat worms, where cell multiplication is muchslower and requires heme from the host. In this setting the dark timemay be 1 to 4 hours.

Pulsing the light source from light (ON) to dark (OFF) can providebenefits from a microbiology perspective and a device-based perspective.From a microbiology perspective, when delivering low-irradiance at ahigher threshold, pulsing the light will effectively reduce the totalnumber of photons delivered and the rate of oxygen and photosensitizercompletion (photosensitizer in this case would refer to photoacceptors,porphyrins, flavonoids, chromophores, etc. already endogenous to thebacteria). The period between dark periods can allow the oxygen levelsand photosensitizer to recuperate, thereby allowing for the treatment tobe performed continuously—over 24 hours to 72 hours or longer. The darkperiod should be sufficiently long to account for the intensity orirradiance delivered by the light-source such that for higherirradiances a slightly longer dark period would be beneficial comparedto lower irradiances, where a slightly shorter dark period would bebeneficial. Simultaneously, the dark period should not be overly longsuch that bacteria are replicating (multiplying) or too short such thatno further bactericidal effects can occur naturally (other than thermaldamage) when the biologically affected area has depleted levels ofoxygen or photo sensitizer elements available such that any photonsdelivered to this area cannot adequately start the ROS process.

Pulsing the light source to go from light to dark has an advantage forthe device delivering the light. Higher irradiance and/or long-durationlight delivery requires significant power to emit light continuously toa given treatment site. Pulsing the light source will turn the light offfor a given time period which will effectively reduce the powerrequired. This aids in the device when it is running off an externalbattery system that requires recharging once the power is depleted. Ifpower is conserved by pulsing the light source, the external battery canmaintain a charge longer while in operation, thereby allowing for alonger time period between recharging the battery by the user.

Pulsing the light source can by symmetric (for example, 5 minutes On and5 minutes Off) or asymmetric (for example, 20 minutes On and 10 minutesOff; or 10 minutes On and 20 minutes Off). The pulsing can consist ofdifferent pulses so that the light intensity changes during the pulse.The pulse can be a square wave, triangle wave, trapezoid wave,sinusoidal wave, etc. The pulsing rate and pulse wave type can change intime during a given treatment. The pulsing rate and pulse wave type canvary for any given wavelength emitted by the device or system. Thepulsing time can be under 1 second, 1 minute, 1 hour, or up to 1 day.

Combination Therapies

Devices and methods disclosed herein can be used with adjunctive oradditional therapeutic modalities, for example, methods described hereincan be used in combination with an antibiotic, for example, antibioticprimary organisms involved in skin/soft tissue infections, which includeStaphylococcus aureus (MRSA methicillin RSA and MSSA methycilllin) andStaph epidermidis. (coagulase-negative Staph). For these types ofinfections, methicillin is most commonly prescribed, followed byvancomycin or doxycycline. As an adjuvant to antibiotic therapy,rifampin is prescribed in conjunction with these drugs given itsanti-biofilm properties for Staph species (it does not kill off thebacteria, but has been shown to penetrate through the biofilm).

In addition to Staph species, the other more significant risk for skinand soft tissue infections is Pseudomonas, which is most often managedthrough Cefepime, Zosyn and Carbapenems.

Methods and devices described herein can be used with drugs from Tables3 and 4, below.

Methods and devices can be used with or without photosensitizers ordyes, for example, photosensitizers from Table 1.

TABLE 1 Dyes and Photosensitizer # Trade Name Molecule 1 ALA5-aminolevulinic acid 2 Foscan Meta-tetra(dyroxyphenyl) chlorin 3 Lu-TexLutetium texaphyrin 4 NPe6 Mono-L-aspartyl chlorin-e6 5 Pc4 Siliconphthalocyanine 6 Photochlor Hexyl ether pyropheophorbide-a derivate 7Photofrin Hematoporphyrin derivative 8 PhotolonChlorin-e6-polyvinylpyrrolidone 9 Photosens Aluminum phthalocyanine 10Purlytin Tin ethyl etiopurpurin 11 TookadPalladium-bacteriopheophorbide)-a 12 Visudyne Benzoporphyrin derivativemonoacid ring A

In addition to the dyes and photosensitizers described in Table 1, otherdyes or photosensitizers include St. John's wort, topical toluidineblue, methyl blue, and all other acridine dyes likely placed on the skinsurface, on the biofilm, or on the wound bed.

Sensors and Processors

In embodiments, the device includes sensors, for example, for monitoringa parameter, for example, at the site of irradiation. For example,responsive to a signal from the sensor indicating, for example, anincrease in temperature, the device or a processor or computer connectedthereto alters an activity. For example, if the temperature rises, thepH drops, and turbidity increases, this signals that an infection isdeveloping and alerts the user.

Pathogens

Devices and methods of the invention can be used against a broadspectrum of pathogens, including bacteria, fungi, protozoans, andparasites. Devices and methods of the invention can be used against grampositive bacteria and gram negative bacteria.

Some pathogens require a higher energy level. Because of heat and otherconcerns, it may be desirable to start with a higher symmetry valuereflecting the need for a higher energy level, but as that pathogen iskilled or neutralized to decrease the symmetry value.

Klebsiella is a gram negative facultative anerobe, and ferments lactose.A relatively higher energy level is needed to kill or neutralize it.Klebsiella lives in a lower O₂ environment, so it may need moreintervening periods. Klebsiella also fixes N, which may deplete freeradicals, making it more difficult to kill or neutralize.

Bacterial pathogens which can be treated with devices and methodsdescribed herein are provided in Table 3. Fungal infections can betreated with devices and methods described herein. Protozoans aretraditionally found in aqueous environments in a wide range of trophiclevels. Parasitic protozoans exhibit osmotrophy, a process by which theyimbibe the nutrients from their environment directly, as they are mostlypresent in nutrient-rich environments. An interesting feature aboutthese parasitic protozoans is their dramatic life cycle. Thereproductive cycle includes short generation times, and alternatesbetween an infective proliferative stage and a dormant cyst stage.Parasitic protozoa that affect humans are provided in Table 2

TABLE 2 Parasitic protozoa that affect humans Entamoeba histolytica(causes amoebiasis) Exoparasites, not related to burn risk: Toxoplasmagondii (causes oxoplasmosis) Cryptosporidium (causes cryptosporidiosis)Trichomonas (causes trichomoniasis) Trypanosoma cruzi (causes Chagasdisease) Leishmania (causes leishmaniasis) Trypanosoma brucei (causesAfrican trypanosomiasis) Naegleria fowleri (causes Naegleriasis)

Parasites will now be discussed in greater detail.

Trypanosoma cruzi. More than 300,000 Americans are infected withTrypanosoma cruzi, the parasite that causes Chagas disease, and morethan 300 infected babies are born every year. Chagas disease istransmitted through a bite from the triatomine bug, which then depositsits feces in the skin opening. Chagas disease can cause long-termdigestive, cardiac, and neurological complications. Death from theinfection is often caused by heart attack. However, if caught early, thecondition is easily cured with medication.

Cysticercosis. This parasitic infection, caused by the taenia soliumtapeworm, makes its home in human tissues such as the brain and muscles.Larval cysts from the parasite form in the body and can cause a numberof complications, including seizures. There are at least 1,000hospitalizations for cysticercosis per year in the U.S. This tapeworminfection is often the result of eating uncooked pork that containslarval cysts.

Toxocara. Approximately, 13.9 percent of the U.S. population hasantibodies against this parasitic infection. Sadly, the rest of us areat risk for acquiring it through roundworms often found in theintestines of dogs and cats. About 14 percent of Americans have hadexposure to toxocara, and at least 70 people die from the infection eachyear. According to the CDC, most of the infections are in children andmany suffer blindness due to related eye disease.

Methods and devices described herein can be used to treat subjectshaving a drug resistant pathogen, for example, a pathogen from Table 3or a pathogen resistant to a drug from Table 3 or 4.

TABLE 3 Bacteria and resistance # Bacteria Type Antibiotics Resistant 1Acinetobacter baumannii Carbapenem 2 Pseudomonas aeruginosa Carbapenem 3Enterobacteriaceae Carbapenem, ESBL-producing 4 Enterococcus faeciumVancomycin 5 Staphylococcus aureus Methicillin-resistant,Vancomycin-intermediate 6 Helicobacter pylori Clarithromycin 7Campylobacter spp. Fluoroquinolone 8 Salmonellae Fluoroquinolone 9Neisseria gonorrhoeae Cephalosporin-resistant, Fluoroquinolone-resistant10 Streptococcus pneumoniae Penicillin-non-susceptible 11 Haemophilusinfluenzae Ampicillin 12 Shigella spp. Fluoroquinolone

TABLE 4 List of Drugs # Drug 1 Ampicillin - Ciprofloxacin 2 Methicillin3 Vancomycin 4 Doxycycline 5 Carbapenem 6 Cefepime 7 Zosyn 8Fluoroquinolone 9 Clarithromycin 10 Cephalosporin 11 Penicillin

Killing organisms requires light, a photosensitizer, and oxygen.Administration of the light at higher irradiance depletes the endogenousphotosensitizer and O₂. In some settings, such as in hypoxic wounds, thelight needs to be pulsed with 2-10 minute dark periods to allow theorganisms to produce photosensitizer and restore the tissue oxygentension. The dark periods may need to be longer for certain parasitesuch as roundworms and flat worms where cell multiplication is muchslower and requires heme from the host. In this setting the dark timemay be 1-4 hours.

Targets for irradiation treatment include burns, ulcers, and points ofpercutaneous entry. The target can be on a surface of the subject, forexample, the skin or the surface of a wound, or the surface of anynatural orifice.

Burn patients' wounds are kept in an aqueous environment to preventdesiccation of the burn wound. Pseudomonas and MRSA are therefore themost common contaminants in these wounds and can cause infection.Pseudomonas thrives in an aqueous environment. In addition, Candidaalbicans is a yeast that can be killed with 405 nm light and is alsovery common in moist environments.

Free radicals that interfere with bata lactamse production, such as VRE,can convert MRSA to make it penicillin sensitivity. The bacteria hasplasmids, they code for small molecules that form Ab resistance. Freeradicals poke holes in the cell membrane. They may also damage the ER.

Targets include natural orifices and the contents thereof, for example,the oral cavity, nasal passages, urethra, anus, vagina, and ears. Thusinfections that enter through, or occur in, a natural orifice can betreated with continuous low-irradiance and the devices that delivercontinuous low-irradiance. Included are infections, for example, bladderinfections and prostatitis where the organisms swims up the urethra, andsinusitis with the organism comes in through the nasal passages, earcanal, etc. Method and devices disclosed herein can be used to treatiatrogenic infections in which the organism gains access through apuncture (intentional or otherwise) made through the skin or othertissue, for example, a puncture occurring with a via or a catheter togenerate infections, for example, central line infections, arthroscopyinfections, etc. or percutaneous implants infections.

Negative Pressure Wound Therapy and Non-Adherent Wound Bed-FacingMembers

Devices described herein can be configured to place the wound bed atsub-atmospheric pressure, sometimes referred to herein as negativepressure wound therapy (NPWT). Unwanted substances, including exudatesthat inhibit healing, or materials that comprise infectious agents, ormediators of inflammation, for example, T cells, B cells, or macrophage,can thus be suctioned away and the amount thereof reduced at the woundbed.

Devices described herein can be configured to comprise a non-adherentmember adjacent to the wound bed. In embodiments this optimizes healing,minimizes, reduces, or inhibits, the growth or level of unwantedorganisms, for example, a bacterium, spore, or fungal element, andminimizes negative effects of dressing changes or device removal.

These embodiments can also be combined. Thus, in embodiments a devicedescribed herein is configured to provide NPWT and a non-adherent memberadjacent to the wound bed.

Components for use in the devices described herein can be adapted fromknown components, see, for example, U.S. Pat. Nos. 8,444,611, 7,857,806,7,534,240, 5,636,643, 9,717,829, 9,642,950, 9,352,076, 9,302,034,9,089,630, 8,772,567, all of which are hereby incorporated by reference.

In an embodiment a light-emitting element, for example, an array of aplurality of light emitting modules, is disposed between the wound bedand a gas-impermeable member which allows a pressure differentialbetween the wound bed, or the space defined by the gas-impermeablemembrane (the reduced pressure space), and ambient atmosphere. Thegas-impermeable member separates the wound or the reduced pressure spacefrom the outside environment, and allows the negative pressure to act onthe area of the wound. In embodiments the gas-impermeable membrane formsa seal with the surface of the subject.

The reduced pressure space is typically configured to be continuous witha vacuum or reduced-pressure source, for example, a suction device, forexample, a pump, or wall suction. The connection to the vacuum sourcecan be controlled, for example, by a valve. The valve or application ofnegative pressure can be under manual control, computer control, orboth. The application of vacuum can be programmed to occur at predefinedtimes, periods, or conditions. The reduced pressure space can beconnected to the source of vacuum by way of a fenestrated tube or disc.

In an embodiment the application of negative pressure is constantthroughout the use of the device or throughout a portion of the time thedevice is contacted with the subject. In embodiments, the device isconfigured to allow different pressures, for example, at different timesof the day, at different stages of treatment or healing, or withdifferent wavelengths of light being applied. For example, in anembodiment a first level of negative pressure is applied at a firstpoint of a preselected period, for example, a 24 hour period, and asecond level of negative pressure is applied at a second point of thepreselected period. In an embodiment a first level of negative pressureis applied at a first stage of healing or treatment, and a second levelof negative pressure is applied at a second stage of healing ortreatment. In an embodiment a first level of negative pressure isapplied during irradiation at a first wavelength, and a second level ofnegative pressure is applied during irradiation with a secondwavelength. In an embodiment a high level of negative pressure (moresuction) is applied during irradiation with a first wavelength and alower level of negative pressure is applied during irradiation with asecond wavelength. In an embodiment the first wavelength is shorter thanthe second wavelength, for example, the first wavelength comprises lightin the blue region of the spectrum and the second wavelength compriseslight in the red region of the spectrum. Control of pressure can beeffected automatically or manually. Control can be effected by a device,for example, a device comprising a computer or microprocessor, whichdevice can also control other parameters, for example, wavelength,intensity, temperature, and the like.

Application of vacuum can be continuous or intermittent. In anembodiment negative pressure is provided at between −75 mm Hg to −125 mmHg.

Devices described herein, for example, devices configured for providingnegative pressure at the wound bed, can include a non-adherent memberdisposed adjacent to or in contact with the wound bed, for example,disposed between the subject, for example, the wound bed, and otherelements of the device, for example, an array of a plurality of lightemitting modules. In embodiments the non-adherent member minimizesfibroblast, keratinocyte, or other cell growth into the device or acomponent of the device such as the non-adherent member. In embodimentsgrowth into the non-adherent member is minimized as compared to what isseen with a porous material, for example, an open cell foam or gauze.The non-adherent member allows separation from the wound bed, forexample, in changing a dressing, or removal or adjustment of a devicedescribed herein with minimized removal of new cells. In an embodimentuse of a non-adherent member, or other material that minimizes opencells, minimizes bacterial growth, which can occur in the cells ofporous materials.

Non-adherent members, for example, a light-emitting element, forexample, an array of a plurality of light-emitting modules, can comprisea synthetic rayon mesh material, a closed-cell foam, or low-surfacecoatings and materials. In embodiments the non-adherent member comprisesa woven element, for example, gauze, coated with a non-adherentmaterial, for example, Teflon® or polytetrafluoroethylene. In anembodiment a non-adherent member comprises a Telfa® coated woven mesh orother element.

A non-adherent member can be separate from, or integral with, anotherelement of the device, for example, a light-emitting member or array,for example, hexagonal members. In an embodiment a light emittingelement, for example, an array of a plurality of light-emitting modules,has a non-adherent member, for example, a layer, disposed, for example,formed or coated on, a surface that faces the wound bed. Thenon-adherent member can be disposed, for example formed or coated,directly on the light-emitting surface of a light-emitting array, or onan additional optical layer disposed on the light-emitting array. In anembodiment the device comprises an array of light-emitting moduleshaving a non-adherent surface exposed to the wound bed, an absorbentelement positioned to accept exudate or other liquid produced or presentat the wound bed, and an element that seals the device with the subjectallowing for the maintenance of negative pressure at the wound bed.

The non-adherent member can comprise a closed-cell foam or othernon-adherent material, including porous materials provided with, forexample, coated with, a non-adherent surface.

In embodiments the light-emitting array comprises an element, forexample, a coating, for example, a conformal coating, that inhibitscontact of liquid, for example, water, with the light-emitting array orcomponents thereof. This can inhibit damage by liquid, water, or otherenvironmental corruption. The layer, for example, a conformal coating,can be used in conjunction with other non-adherent layers.

In an embodiment, an element of a device described herein, for example,a non-adherent member or element, for example, a light-emitting arraywhich comprises a non-adherent surface, can be configured to allow fluidtransfer, for example, transfer away from the wound bed. For example,the element can comprise one or a plurality of conduits or channels, forexample, holes, which provide for transfer of liquid away from the woundbed. A conduit, channel, or hole can be several micrometers tomillimeters in diameter or perimeter. In an embodiment the devicecomprises a reservoir to receive transferred liquid. The reservoir cancomprise an absorbent member, for example, which can comprise open cellfoam or gauze-like materials. In an embodiment the reservoir is disposedon the surface of the light-emitting array that does not face the woundbed and the light-emitting array is configured to channel fluid awayfrom the wound bed to the reservoir. In an embodiment the reservoir, forexample, open cell foam or gauze, is attached to the light-emittingarray by direct contact and application of a gas-impermeable member, forexample, a drape/semi-occlusive dressing, to create a seal for NPWT. Inan embodiment a reservoir, for example, open cell foam or gauze, isadhered, for example, by an acrylic or silicone adhesive, to the back(non-wound side) layer of the light-emitting array. Distal to the woundbed, on the side of the light-emitting array that does not face thewound, a gas-impermeable member, for example, a drape or semi-occlusivedressing is used to seal the wound for NPWT.

In an embodiment the light-emitting array, for example, acts as a single“non-adherent” surface in a NPWT dressing. This allows forepithelization to occur without disrupting new growth. In an embodiment,the non-adherent light-emitting array provides anti-microbiallight-based effects to the wound site and to the liquid, for example,exudate, disposed in or traveling throughout the pores of the deviceinto a reservoir, for example, a reservoir comprising open-cell foam orgauze. The light from the light-emitting array can decrease the rate ofcolonization of bacteria and formation of biofilms in both the wound bedand adjacent materials that interact with the wound. Thus, inembodiments, wound healing, for example, the rate of wound healing, isoptimized.

Some embodiments are discussed in more detail below.

FIGS. 22 and 23 show elements of an exemplary device 2200 from the sideprofile and top view, respectively. The hexagon light guide is discussedearlier, but the electronics include LEDs, LED drivers, resistors, andother electrical circuits reside on PCB layers with copper tracesconnecting the circuitry to an external power source. The PCB layers aretypically made of polyimide of varying thicknesses from 10 microns to 1millimeter or thicker, and the layers can be composed of varying color.A white layer is chosen where the hexagon light guide is positioned.This white layer could potentially be used as a white reflectivesubstrate to bounce the light from the LEDs emitting light from a sideof a hexagon light guide. The electronics and optics are kept in placewith several strategic adhesive zones. The electronics and optics aresandwiched between various diffusers, reflectors, and foams which can behydrophobic (repel fluids) or hydrophilic (absorb fluids).

In FIG. 23, the view is a top view; however the most immediate layer isnearest to the skin. An element that can be used instead of epoxy 2300(green color rectangles labeled in FIG. 23) over the LEDs 2302 (LEDarray, yellow color rectangles labeled in FIG. 23) is either a white PETopaque material to cut down or reduce stray light coming from the sideemitting LEDs which is not directly projected into the hexagon lightguides 2304 (light blue colored hexagons labeled in FIG. 23).Alternatively, the epoxy can be substituted with a resin which can betransparent, or coated or embedded with a diffusive material likereflective glass or plastic beads (Cospheric Solid Soda Lime GlassMicrospheres 2.5 g/cc d50˜4 um—Uncoated) which can cut back on straylight but also allow the light to be equal in irradiance (or designerspecific light output based on effective use case desire) to theirradiance at the center or non-LED array edge of the hexagon lightguide arrays.

FIGS. 24 and 25 show a side and top view profile of an embodimentcomprising a NPWT vacuum dressing 2400. All the electronic and opticalcomponents are water proofed and the most immediate layer making contactwith the skin can be either hydrophobic or hydrophilic. An exemplaryoption is for the layers in direct contact with the top or bottom of theelectronics and optics contain hydrophobic foam 2402 (see white foamlayer by the skin and layer C. in FIG. 24). Fluid from the wound iswicked away or is directed through fluid flow channels 2404 (yellowchannels shown in FIG. 24) which reside on the corners of adjacenthexagons 2406 (yellow channels shown in FIG. 25). In FIG. 24, Layer A ismade of the typical NPWT hydrophilic foam, which takes in the fluid fromthe wound that has traveled past the hexagon electronics and light guidearray. The vacuum dressing layer takes the fluid and transports it tothe vacuum canister.

FIG. 26 shows an example application of the embedded hexagon electronicsand light guide array 2600 (also referred to as the light-emittingantimicrobial layer) with the foam and semi-occlusive dressing in a NPWTvacuum dressing on an wound with fluids and exudate. Fluid 2602 (yellowarrows) flows into the dressing through the “Fluid Flow Channels” in thehexagon electronics and light guide array area up into the hydrophilicfoam which is in direct contact with the tubing and section of thevacuum system. Simultaneously, the hexagon electronics and light guidearray are projecting out light, quantified as irradiance, at variouswavelengths, specifically 405 nm (+/−10 nm) into the wound bed 2604(blue and white dotted arrows). The light acts as an antimicrobial,killing bacteria, fungi, spores, and other infectious-related substancesand materials that impact wound healing.

In some embodiments discussed above, hexagon light guides andcorresponding electronics layouts are described. Table 5 indicatesexemplary design parameters for components of the hexagon light guidesand corresponding electronics layouts described above.

TABLE 5 Exemplary Design Parameters Bend PCB Hexagon Radius of ThicknessMaximal Curvature Min. Air Max. Air LEDs Spacing LED Half (mm) Width(mm) (mm) Gap (mm) Gap (mm) Per Side of LEDs Angle (Deg.) 1.6 5 25 1.223.41 1 Equal 55 1.6 5 50 1.11 3.30 1 Equal 55 1.6 5 100 1.05 3.24 1Equal 55 1.6 5 250 1.02 3.21 1 Equal 55 1.6 20 25 1.75 2.75 3 Equal 551.6 20 50 1.43 2.43 3 Equal 55 1.6 20 100 1.22 2.22 3 Equal 55 1.6 20250 1.09 2.09 3 Equal 55 1.6 50 25 2.56 5.24 5 Equal 55 1.6 50 50 1.954.64 5 Equal 55 1.6 50 100 1.53 4.22 5 Equal 55 1.6 50 250 1.22 3.90 5Equal 55 0.8 5 25 1.14 3.33 1 Equal 55 0.8 5 50 1.07 3.26 1 Equal 55 0.85 100 1.03 3.22 1 Equal 55 0.8 5 250 1.01 3.20 1 Equal 55 0.8 20 25 1.482.48 3 Equal 55 0.8 20 50 1.27 2.27 3 Equal 55 0.8 20 100 1.14 2.14 3Equal 55 0.8 20 250 1.06 2.06 3 Equal 55 0.8 50 25 1.99 4.68 5 Equal 550.8 50 50 1.61 4.30 5 Equal 55 0.8 50 100 1.34 4.02 5 Equal 55 0.8 50250 1.14 3.83 5 Equal 55

EXAMPLES Example 1: Methicillin-Resistant Staphylococcus Aureus Killing

Phase 1: The experimental setup of the study in Phase 1 involvedcultures of methicillin-resistant Staphylococcus aureus (MRSA) suspendedin Tryptic Soy Broth (TSB), and prepared to densities of 105 colonyforming units per milliliter (CFU/mL), as confirmed through measurementof the solutions' optical densities (OD600), as well as through standardplate counts. Two hundred seventy-five microliters (275 μL) of thesuspended cultures were loaded into each well of a 24-well microplate toreceive light exposure. A total of four microplates were used in a giventrial, wherein the microplates were randomly assigned to one of thefollowing cohorts: (1) Control Microplate (Receiving No LightTreatment); (2) 75 J/cm² LIMB system delivered over 2 hours (10.44mW/cm² irradiance); (3) 75 J/cm² LIMB delivered over 4 hours (5.22mW/cm² irradiance); and (4) 75 J/cm² LIMB system delivered over 6 hours(3.48 mW/cm² irradiance). To ensure that each well within a givenmicroplate was receiving identical irradiances, a THORLABS Optical PowerMeter (Thor Laboratories, Newton, N.J.) was placed over each well toquantitate the exact irradiance being delivered. Throughout the courseof this experiment, there were three separate trials conducted to ensureconsistency and to evaluate both the intraplate and interplatebactericidal effects. During each trial, the optical density at 600 nm(OD600) of the cultures was recorded at baseline and followingtreatment. Additionally, fifty-microliter aliquots were taken from fourrandomly selected wells during those increments to be asepticallytransferred onto Tryptic Soy Agar (TSA) plate using a Whitley AutomatedSpiral Plating system for analysis. Data throughout the course of thisstudy was analyzed post-hoc using an ANOVA (a=0.05) followed by atwo-sided t-test. Each illumination condition was compared to both theircontrol and accompanying experimental conditions. P values <0.05 wereconsidered to be statistically significant.

FIG. 13 illustrates a chart 1300 which indicates viability of MRSAclinical isolates following exposure to 75 J/cm² LIMB system at varyingirradiances and exposure durations. Statistical analysis was conductedpost-hoc, and consisted of ANOVA and two-sided t-test. Asterisksidentify statistically significant variance (P<0.05) when compared toboth control and experimental conditions.

FIG. 13 indicates that there was a correlation associated with a greaterbacterial load reduction when an identical fluence of 75 J/cm² 405-nmLLLT was administered at a lower irradiance and subsequently anincreased exposure time. A statistically significant bacterial loadreduction was observed when the irradiance was decreased from 10.44mW/cm² and 5.22 mW/cm² (95.71% reduction) to 3.48 mW/cm² (99.63%reduction [p<0.004]).

Based on these statistically significant findings, the antimicrobialpotential of the LIMB system further was evaluated by administeringtreatments over the course of 24 hours at irradiances reduced by as muchas over 1000-fold compared to prior studies. Through this study, it wasdetermined if there was a particular irradiance threshold of the LIMBsystem by exposing MRSA cultures to irradiances of: 145 μW/cm²; 290μW/cm²; 580 μW/cm²; 1.16 mW/cm² and 2.31 mW/cm². Through this matrix ofconditions each culture received the LIMB system for 24 hourscontinuously. During each trial, the optical density at 600 nm (OD600)of the cultures was recorded at baseline and in 6-hour incrementsthroughout the LIMB system treatment. Additionally, fifty-microliteraliquots were taken from four randomly selected wells during thosesix-hour increments to be aseptically transferred onto Tryptic Soy Agar(TSA) plate using a Whitley Automated Spiral Plating system foranalysis. Data throughout the course of this study was analyzed post-hocusing an ANOVA (α=0.05) followed by a two-sided t-test. Eachillumination condition was compared to both their control andaccompanying experimental conditions. P values <0.05 were considered tobe statistically significant.

FIG. 14 illustrates a chart 1400 which indicates the viability of MRSAclinical isolates following exposure to the LIMB system continuously for24 hours at varying irradiances. Aliquots were collected from eachtreatment condition in 6-hour increments throughout the course of the 24hour exposure periods. Statistical analysis was conducted post-hoc, andconsisted of ANOVA and two-sided t-test. Asterisks identifystatistically significant variance (P<0.05) when compared to bothcontrol and experimental conditions.

As illustrated in FIG. 14, continuous delivery of the LIMB system for 24hours at each of the tested irradiances (145 μW/cm²-2.31 mW/cm²)provided a statistically significant reduction of MRSA bacterial densitywhen compared to the control, untreated aliquots. In addition, it wasdetermined as early as 6 hours across all three replicate trials, thatthere was a statistically significant (p<0.001) variation in thereduction of aliquots treated at 1.16 and 2.31 mW/cm² among the otherirradiance ranges, respectively. This finding suggests that there ispotentially a discrete range for continuous LIMB system delivery, andthat irradiances below said range could demonstrate limitedantimicrobial efficacy. Therefore, based on initial criteria, thelowest-irradiance to administer an antimicrobial LIMB system and achievea minimum of 99.0% bacterial load reduction was 1.16 mW/cm².

Upon completion of Phase 1, a discrete dose-range can be optimized inPhase 2 to deliver a minimum 2.0 log (99.0%) bacterial load reductionwithin a single LIMB system treatment of the followingmultidrug-resistant organisms (MDROs): MRSA, Pseudomonas aeruginosa (P.aeruginosa), carbapenem-resistant Klebsiella pneumoniae (CRE), New Delhimetallo-beta-lactamase K. pneumoniae (NDM-1) and Vancomycin-resistantEnterococcus faecium (VRE).

To validate the antimicrobial effects of LIMB system at this particulardosimetry for both Gram Positive and Gram Negative MDROs, samples of P.aeruginosa were first treated under the identical parameters outlined inFIG. 14 and observed a bacterial load reduction of 99.21% [p<0.001compared to control species] at irradiances as low as 1.16 mW/cm².Following this procedure, the bactericidal properties of LIMB system oneach of the aforementioned MDROs can be investigated at irradiancesranging from 2.78 mW/cm²-8.33 mW/cm² (at fluences ranging between240-720 J/cm²) delivered over a period of 24 hours.

Example 2: Inhibition of MDRO Colonization

Two hundred microliter (200 μL) aliquots of overnight cultures of P.aeruginosa suspended in Tryptic Soy Broth (at cell density of 105CFU/mL) were loaded into individual wells of a Corning® clear bottom96-well microplate (n=48 wells per organism per plate). Followingbacterial seeding, each microplate was transferred into an incubator at37° C. and 5% CO₂ to allow for optimal bacterial growth conditions.Within each given trial, there were 5 microplates used. Each microplatewas randomly assigned to one of the following conditions within theincubator: (1) Control plate (receiving no intervention); (2) 60 J/cm²LIMB system exposure over 24 hours; (3) 120 J/cm² LIMB system exposureover 24 hours; (4) 240 J/cm² LIMB system exposure over 24 hours; and (5)5.0 mg/L Ciprofloxacin over 24 hours. The LIMB system was deliveredbelow each microplate via a light emitting system with an appropriateheat sink of an embodiment of the disclosure, and was designed ensurelight uniformity across the course of a given treatment. All treatmentparameters were repeated in triplicates to demonstrate intraplate andinterplate consistency.

The rate of bacterial growth and biofilm formation of each experimentalcohort was evaluated at both 18 and 24 hours into therapy. The rate ofbiofilm formation was completed using a Crystal Violet assay, asdescribed by O'Toole. Bacterial growth was monitored using serialdilutions and plating 100 μL aliquots of each experimental parameter onCetrimide Agar plates using the Track Dilution Plating Method todetermine bacterial density (CFU/mL). In order to account for biofilmencapsulated organisms, each well plate was placed on a microplateshaker at 800 rpm for 10 minutes to ensure mechanical disruption of thebiofilm prior to aliquot collection.

FIG. 15 illustrates a graph 1500 indicating delivery of a single cycleof 405 nm LIMB system over a 24 hour time period at irradiances of 1.39mW/cm², 2.78 mW/cm², and 5.56 mW/cm² on cultures of P. aeruginosa ingrowth conditions of 37° C. and 5% CO₂. A crystal violet stain wascompleted on the cultures throughout the course of treatment todemonstrate the formation of microbial biofilms. Assay performed:Crystal Violet Stain.

FIG. 16 illustrates a chart 1600 indicating a delivery of a single24-hour cycle of LIMB system at fluences of: 60 J/cm²; 120 J/cm² and 240J/cm², and exposure to ciprofloxacin (5 mg/L) on cultures of P.aeruginosa in growth conditions of 37° C. and 5% CO₂. Aliquots werecollected upon completion of treatment, and were analyzed usingsonication and serial dilution to determine the percent reduction ofviable P. aeruginosa organisms in both control and treated-samples.

As illustrated in FIGS. 15 and 16, delivery of the LIMB system atvarying irradiances to planktonic cultures of P.aeruginosa for 24 hoursprovided a statistically significant inhibition of bacterialcolonization (>99.0% reduction) and biofilm density when compared to thecontrol, untreated aliquots (p<0.05). In addition, it was determinedthat administration of the LIMB system at higher energy levels (240J/cm²) provided a statistically similar antimicrobial response asCiprofloxacin (p >0.10) in regards to biofilm formation and bactericidalproperties. These finding suggests that administration of the LIMBsystem holds the potential to delay the onset of bacterial colonizationand biofilm formation through a mechanism with comparable efficacy toclinical relevant antibiotic agents.

Example 3: Reduction and Elimination of Biofilms in Wounds

Two hundred microliter (200 μL) aliquots of overnight cultures of P.aeruginosa suspended in Tryptic Soy Broth (at cell density of 105CFU/mL) were loaded into individual wells of a Corning® clear bottom96-well microplate (n=48 wells per organism per plate). Followingbacterial seeding, each microplate was transferred into an incubator at37° C. and 5% CO₂, and was allowed to grow under static conditions foreither 24 or 48 hours. Prior to initiation of the LIMB system orCiprofloxacin exposure, the growth media from each biofilm wasdiscarded, and the biofilms were carefully rinsed with 200 μL phosphatebuffered saline (PBS).

Within each given trial, there were 5 microplates used. Each microplatewas randomly assigned to one of the following conditions after growingfor 24 hours: (1) Control plate (receiving no intervention); (2) 120J/cm² LIMB system exposure over 24 hours; (3) 240 J/cm² LIMB systemexposure over 24 hours; (4) 360 J/cm² LIMB system exposure over 24hours; and (5) 5.0 mg/L Ciprofloxacin over 24 hours. The LIMB system wasdelivered below each microplate via a light emitting system with anappropriate heat sink developed, and was designed ensure lightuniformity across the course of a given treatment. All treatmentparameters were repeated in triplicates to demonstrate intraplate andinterplate consistency.

The rate of bacterial growth and biofilm formation of each experimentalcohort was evaluated at both 18 and 24 hours into therapy. The rate ofbiofilm formation was completed using a Crystal Violet assay, asdescribed by O'Toole. Bacterial growth was monitored using serialdilutions and plating 100 μL aliquots of each experimental parameter onCetrimide Agar plates using the Track Dilution Plating Method todetermine bacterial density (CFU/mL). In order to account for biofilmencapsulated organisms, each well plate was placed on a microplateshaker at 800 rpm for 10 minutes to ensure mechanical disruption of thebiofilm prior to aliquot collection.

FIG. 1700 illustrates a graph 1700 which indicates delivery of a singlecycle of 405 nm LIMB system over a 24 hour time period at fluences of120 J/cm²; 240 J/cm² and 360 J/cm² on P. aeruginosa biofilms previouslygrown for 24 hours at 37° C. and 5% CO₂. The LIMB system exposure wascompleted at room temperature. A crystal violet stain was completed onthe cultures throughout the course of treatment to demonstrate theremaining fraction of microbial biofilms.

FIG. 18 illustrates a chart 1800 indicating delivery of a single cycleof the LIMB system over a 24 hour time period at fluences of 120 J/cm²;240 J/cm²; and 360 J/cm², as well as ciprofloxacin concentrations of 5mg/L; 500 mg/L; and 5 g/L on P. aeruginosa biofilms previously grown for24 hours at 37° C. and 5% CO₂. The LIMB system exposure was completed atroom temperature. A crystal violet stain was performed upon completionof each condition to demonstrate the remaining fraction of microbialbiofilms. Statistical analysis was conducted post-hoc, and consisted ofANOVA and two-sided t-test.

FIGS. 17 and 18 demonstrate the antimicrobial properties of the LIMBsystem in comparison to Ciprofloxacin therapy following 24 hour exposureat varying treatments. It was also determined in FIG. 18 thatsignificant variance (p<0.001) was observed among control biofilms andall experimental conditions. Furthermore, significant variance (p<0.05)was observed when comparing 500 mg/L ciprofloxacin treated biofilms towhen compared to biofilms treated with 5 g/L ciprofloxacin and 240 and360 J/cm² LIMB system, respectively.

Example 4: Disruption of Biofilms

Two hundred microliter (200 μL) aliquots of overnight cultures of P.aeruginosa or MRSA suspended in Tryptic Soy Broth (at cell density of105 CFU/mL) were loaded into individual wells of a Corning® clear bottom96-well microplate (n=24 wells per organism per plate). Followingbacterial seeding, each microplate was transferred into an incubator at37° C. and 5% CO₂ to allow for optimal bacterial growth conditions.Within each given trial, there were 2 microplates used. Each microplatewas randomly assigned to one of the following conditions within theincubator: (1) Control plate (receiving no intervention); (2) LIMBsystem exposure over 24 hours. The LIMB system was delivered below eachmicroplate via a light-emitting system with an appropriate heat sinkdeveloped, and was designed to ensure light uniformity across the courseof a given treatment. All treatment parameters were repeated intriplicates to demonstrate intraplate and interplate consistency. Allimages were evaluated using a FilmTracer LIVE/DEAD® Biofilm ViabilityKit (Invitrogen) upon completion of the exposure periods, and werequantitatively analyzed using the program Comstat 2.1 through ImageJ.

FIG. 19 illustrates a chart 1900 indicating quantitative analysis ofLive/Dead Confocal Microscopy Staining of mature P. aeruginosa and MRSAbiofilms exposed to a single LIMB system treatment over 18 hours. MeanBiomass ratios were collecting using the biofilm analysis softwareComstat 2.1®, and this ratio serves as a direct measurement of presenceof live and intact microbial biofilms.

FIG. 20 illustrates an image 2000 of a Live/Dead Staining Assay of MRSA(A-B) and P. aeruginosa (C-D) following LIMB system treatment. A) MRSAand C) P. aeruginosa Control Groups, Receiving Sham Light Treatment; B)MRSA and D) P. aeruginosa following the LIMB system over 18 hours.(Green indicates intact cell membrane and Red indicates damaged/lysedmembranes).

FIG. 19 demonstrates that a single treatment of the LIMB system provideda statistically significant reduction (p<0.01) in microbial biomass whencompared to control, non-illuminated biofilms. These findings, derivedfrom confocal analysis illustrated in FIG. 8, support the underlyingmechanism of action of the LIMB system, and suggest that the LIMBsystem's capabilities to penetrate through microbial biofilms can serveas a promising adjuvant to conventional antibiotics rendered otherwiseineffective in biofilms.

To further evaluate this theory, a matrix of three discrete LIMB systemdoses (240 J/cm² [irradiance 2.78 mW/cm²]; 240 J/cm² [irradiance 5.56mW/cm² and 480 J/cm² [5.56 mW/cm²]) was delivered in conjunction withvarying concentrations of Ciprofloxacin (5 μg/mL; 0.5 mg/mL and 5 mg/mL)on P. aeruginosa biofilms.

FIG. 21 illustrates a chart 2100 indicating a delivery of a single cycleof 405 nm LIMB system over a 24 hour time period at fluences of 240J/cm²; and 480 J/cm² in the presence and absence of Ciprofloxacin on P.aeruginosa biofilms previously grown for 24 hours at 37° C. and 5% CO₂.The LIMB system exposure was completed at room temperature. A crystalviolet stain was completed on the cultures to demonstrate the remainingfraction of microbial biofilms. Statistical analysis was conductedpost-hoc, and consisted of ANOVA and two-sided t-test. Asterisksidentify statistically significant variance (p<0.05 or p<0.001) whencompared to both control and experimental LIMB system conditions withina given Ciprofloxacin cohort.

FIG. 21 demonstrates that across each Ciprofloxacin concentrationemployed, there was a statistically significant (p<0.05) reduction of P.aeruginosa biofilm at all three discrete LIMB system fluences.

Discussion will now be directed to light guides and Light Guide Films(LGFs). A light guide or LGF is a device designed to transport lightfrom a light source to a point at some distance with minimal loss. Lightis transmitted through a light guide by means of total internalreflection (TIR). Light guides are usually made of optical gradematerials such as acrylic resin, polycarbonate, epoxies, and glass. Alight guide can be used to transmit light from an LED lamp on a PrintedCircuit Board (PCB) to a front panel for use as status indication, canbe used to collect and direct light to backlight an LCD display orlegend, and can be used as the means to illuminate a grid pattern on asee-through window. For the purposes of certain products, the LGF isused to create precision Light Emitting Surfaces (LES) to deliver exact,within +/−20% of the mean irradiance (mW/cm²), uniform light of one ormore wavelengths to a therapy site. Uniformity is crucial to guaranteeall locations in the treatment site receive identical illumination andreduce variability in treatment and treatment outcomes.

Light delivery in a LGF is achieved similar to the principal behind LEDedge-lit displays. In short, LEDs are placed in a sideways orientationand coupled to a thin, optically clear material with a surface patterndesign to extract light in a specific way from the material.

One feature of light delivery through an LGF is taking advantage of TIRand the critical angle where light within a higher index of refractionmedium or material is surrounded by a lower index of refraction mediumor material. For example, FIG. 27 illustrates a schematic diagram 2700illustrating light behavior at a material boundary. As illustrated byFIG. 27, the higher index of refraction medium is water surrounded bythe lower index of refraction medium of air.

When light traveling through the higher index of refraction materialhits the boundary of the material at an angle less than the criticalangle, the light primarily refracts out of the material into the lowerindex of refraction material. If the light hits this boundary at anangle greater than the critical angle, the light total internallyreflects within the higher index of reflection material, as if theboundary of the material acts like a mirror, where the light reflects atthe same angle as when it hit the material boundary.

The critical angle (f_(c)) can be determined using Equation 1,

$\begin{matrix}{{\sin \mspace{14mu} f_{c}} = \frac{n_{f}}{n_{i}}} & (1)\end{matrix}$

where n_(f) is the low (typically outside) index of refraction materialand n_(i) is the high index of refraction material.

Once light within the higher index of refraction material has met theTIR condition from having an angle larger than the critical angle, thislight can be trapped in this material (a/k/a the propagation material)and continue to bounce off each side of the material boundaries like amirror as long as several conditions are met, primarily: a) the top andbottom boundaries remain flat and parallel to one another; b) the indexof refraction of materials surrounding the propagation material remainslower than the index of refraction of the propagation material; or c) ifone or both sides of the propagating material are surrounded byminor-like reflection materials that will bounce any refracted lightback into the propagation material. For example, see FIG. 28, whichillustrates a schematic diagram 2800 of TIR conditions wheren_(f)<n_(i).

In regard to creating uniform light delivery across an LGF, methods toallow light rays that are trapped by TIR to reach a condition in whichthe ray's angle becomes less than the critical angle and can escape theLGF are disclosed herein. One simple method of creating this effect isto create surface features that present controlled or random angles tothe light rays in the propagating material. In many cases a whitereflective PET layer is used to create an efficient mirror like surface(reflectance up to 98%) on the bottom (non-light-emission-side) of theLGF and to have a top-most layer with a diffuser layer which hasnanometer or micrometer sized features to disrupt the angular context ofthe light. For example, see FIG. 29, which illustrates a schematicdiagram 2900 of disrupting TIR within an LGF.

These nanometer and micrometer structures can be applied to the LGFpropagating materials in many different forms including diffusionmaterials or sheets laid on top of the propagating material.Alternatively, the nano- and micro-structures can be embossed or curedonto the propagating material. Regarding the reflective materialtypically used on one side of the LGF, other highly reflective mirrorlike substrates can be substituted for the white reflective PET layersuch as silver foil or a white painted surface.

Typically, the objective of using an LGF as a light delivery source isto create a uniform light distribution across the output interface. Asmentioned, creating surfaces that bend the light inside the LGF to fallunder the critical angle for TIR allows the light to exit. However, ifthe surface for disrupting the ray angles is too extreme, too much lightcan exit the LGF on the side closest to the light source (side-emittingLEDs) and result in little light exiting the opposite side of the LGFresulting in a non-uniform light distribution field across the LES.

To generate a more uniform light distribution over a large surface area,when dealing with a one-dimensional LGF where light is only deliveredalong one input face (as seen in FIG. 29 and FIG. 30, discussed below),the nanostructures or microstructures, as one moves away from the lightinput surface, need to vary in size, going from larger and deeperstructures closest to the light input and smaller and shallowerstructures furthest away from the light input. Additionally, the spacingor density between structures ideally becomes tighter the further awaythe structure is from the light input source. For example, FIGS. 30 and31 show an example of the microstructure size and location as thestructure moves further from the light source.

More specifically, FIG. 30 is a schematic diagram 3000 of microstructuresize and location. With reference to FIG. 30, micro dots or micro lensesare considered structures that disrupt light ray angles inside the LGFthat will allow rays to slowly break the critical angle and TIRconditions. By varying the structure in size and location across theLGF, light exitance can be more precisely controlled to create a uniformlight output surface. FIG. 31 is a schematic diagram 3100 ofmicrostructure size and location according to another embodiment. Withreference to FIG. 31, the micro dot or micro lens structures can beimprinted on either the front or back side of the LGF. The structurescan be convex, concave, or a combination of varying shapes.

An alternative to a one-dimensional or one-sided light source-based LGFis to have light enter the LGF from multiple input faces. An advantageof this approach is to address the limited efficiency from theside-emitting light sources when more light output is required from thelight-emission surface and to account for optical light losses that mayoccur over the length of travel in the LGF. An example of a multisidedillumination input interface LGF is shown in FIG. 32. FIG. 32illustrates a schematic view 3200 of multiple-sided light input sourcesaccording to an embodiment.

Light input can come from multiple sides. In a multi-sided light inputinterface, such as the embodiment illustrated in FIG. 32, the nanometerand micrometer scale structure size and density will be two-dimensional,dependent upon the LGF shape. For example, the size of the structureswill be larger and deeper closest to the illumination sources and in thecenter of the LGF, smaller and deeper. The density of the structureswill increase as the structures move closest to the illumination sourceto the center of the LGF. If the LGF has light source input from morethan 2 sides, the likely structural pattern is radial with structuresbecoming smaller and denser the further the structures are from thelight input sources.

There are several techniques to create the nanometer and micrometersized structures for the LGF. The simplest approach with very littleprecision is to roughen the surface. Sample production of this techniquecan be demonstrated on one surface of the propagating material withsandpaper. For more precision using this technique, another possiblesetup is to bring up small rough-surfaced dots on one side of thepropagating material. The dots can be created with typicalsanding/etching processes.

For more precision and to match with current optical design and modelingtools is to use modern manufacturing technologies with electron beamlithography, direct laser beam lithography, or diamond turning. Each ofthese techniques enables highly accurate tooling of nanostructures andmicrostructures. The preferred approach is using a nickel electroformingapproach for tooling since it enables cost effective copy tools for massproduction, while preserving nanoscale accuracy. Table 6 providesspecifications for each of the processes that are generally availablefor LGF manufacturing.

TABLE 6 Precision Manufacturing Processes and Specifications forNanostructures and Microstructures. Electron Beam Direct Write LaserLithography Lithography Diamond Turning sub-micron structures, structuresize over a micrometer scale feature sizes less than micrometerstructures 100 nm binary/continuous circular/1- binary/multilevel/structure profile dimensional line continuous structure patterned areaup to patterns profiles 45 cm squared v-groove/triangle typicalpatterned area typical structure structure profiles up to 15 squaredepth <15-20 um small acute angle centimeters radius a high typicalstructure optical quality depth <1-2 um structure depths deeper than 1-3um

In low-volume production a master tool—a reverse imprint of thenanostructures and microstructures or, depending on the replicationtechnique, the positive version of the structures—will be made and thenembossed using standard techniques and tools into embossing material,such as UV-curable lacquer, that resides on a base substrate material,like transparent PET/PC/PMMA/TPU. Together the embossed structurecoating and the substrate film make up the LGF, as illustrated in FIG.33. FIG. 33 illustrates a schematic view 3300 of an LGF, a combinationof an embossed structure coating with a substrate film. The removableprotective film of FIG. 33 is applied to protect the structures prior todeployment/use.

In large-scale production, roll-to-roll production is a preferred massmanufacturing technology for nanostructures and microstructures,offering cost efficiency and nanometer accuracy. Again, as in thelow-volume production process, the nanostructures and microstructuresare printed on a UV-curable lacquer on a substrate film. Typically, allLGF production is performed in a cleanroom with machine vision andindividual component markings to ensure controlled manufacturing.Cutting of parts is typically performed with precision die-cutting orlaser-cutting.

Enumerated Embodiments Method of Treating a Subject

1. A method of treating a subject, the method comprising:

irradiating the subject with light having a wavelength between 380 nmand 500 nm, for example, at 405 nm, at.25 to 25 milliWatts/cm²,

wherein the irradiation is for a time sufficient to treat a subject, andwherein treating comprises:

a) treating a subject at risk for a pathogen infection;

b) treating a subject having a pathogen infection;

c) preventing the infection by a pathogen;

d) reducing the level of a pathogen;

e) reducing the virulence of a pathogen in the subject, for example,reducing its ability to damage the subject, slowing the growth of thepathogen, or reducing the release of a toxin by the pathogen;

f) reducing or otherwise ameliorating an unwanted manifestation ofinfection by a pathogen;

g) reducing the level or transmission of a transmissible nucleic acid,for example, a plasmid or an RNA, by a pathogen, for example, to asecond pathogen; or

h) modulating, for example, inhibiting, reducing, or degrading thestructure or integrity an extracellular matrix;

i) modulating the microbiome of the subject, for example, at the site ofirradiation or at site outside the site of irradiation, for example,reducing one or more members of a polymicrobial community; or

j) irradiating a site at which a device, for example, a catheter orconductor, enters the subject's body.

2. The method of numbered embodiment 1, further comprising treating asubject at risk for a pathogen infection.

3. The method of any of numbered embodiments above, further comprisingtreating a subject having a pathogen infection.

4. The method of numbered embodiment above, further comprisingpreventing the infection by a pathogen, of a subject.

5. The method of numbered embodiment above, further comprising reducingthe level of a pathogen in a subject.

6. The method of any of numbered embodiments above, further comprisingreducing the virulence of a pathogen in the subject, for example,reducing its ability to damage the subject, slowing the growth of thepathogen, or reducing the release of a toxin by the pathogen.

6b. The method of any of numbered embodiments above, further comprisingreducing or otherwise ameliorating an unwanted manifestation ofinfection by a pathogen.

7. The method of any of numbered embodiments above, further comprisingreducing the level or transmission of a transmissible nucleic acid, forexample, a plasmid or an RNA, by a pathogen, for example, to a secondpathogen.

7a. The method of any of numbered embodiments above, wherein thetransmissible nucleic acid comprises a sequence that confers resistanceto an antibiotic.

7b. The method of numbered embodiment any of above, further comprisingmodulating, for example, inhibiting, reducing, or degrading anextracellular matrix, for example, a biofilm, for example, in the areairradiated.

7c. The method of any of numbered embodiments above, further comprisingincreasing the porosity of a biofilm, for example, increasing theporosity to a drug, for example, an antibiotic.

7d. The method of any of numbered embodiments above, further comprisingmodulating, for example, inhibiting, reducing, or degrading thestructure or integrity a biofilm, for example, forming fenestrations inthe biofilm.

7e. The method of any of numbered embodiments above, further comprisingmodulating the microbiome of the subject, for example, at the site ofirradiation or at site outside the site of irradiation for example,decreasing the proportion or numbers of a first microbe, for example, apathogen, for example, MRSA, VRE, and optionally, increasing theproportion of numbers of a second microbe, for example, a non-pathogen,for example, Lactobacillus.

7f. The method of any of numbered embodiments above, further comprisingirradiating a site at which a device, for example, a catheter orconductor, enters the subject's body.

8. The method of any of numbered embodiments above, wherein the subjecthas a wound.

8a. The method of any of numbered embodiments above, wherein the subjecthas an acute wound such as a trauma, surgical, or burn wound.

8b. The method of any of numbered embodiments above, wherein the subjecthas a chronic wound such as from decubitus, pressure, diabetic, venousstasis ulcers.

8c. The method of any of numbered embodiments above, wherein the subjecthas compromised renal function, for example, renal function that hasbeen impaired by a disorder or a medical treatment, for example,antibiotic treatment.

8d. The method of any of numbered embodiments above, wherein the subjecthas compromised hepatic function, for example, hepatic function that hasbeen impaired by a disorder or a medical treatment, for example,antibiotic treatment.

9. The method of any of numbered embodiments above, wherein the subjecthas a burn, for example, a burn that is greater than a Grade 1 burn, forexample, a superficial first-degree burn of the epidermis, or outerlayer of skin.

9a. The method of any of numbered embodiments 1-9, wherein the subjecthas a burn, for example, a burn that is greater than a Grade 1 Burn,covering at least 1%, 10%, 50%, or 100% of Total Body Surface Area(TBSA).

9b. The method of any of numbered embodiments 1-9, wherein the subjecthas a burn, for example, a burn that is greater than a Grade 1 burn,covering 1% to 100%; 5% to 80%; or 10% to 50%, of TBSA.

10. The method of any of numbered embodiments 1-9b, wherein the subjectis less than 1, 2, 5, 10, 18, 30, 50, 60 75 or 100 years of age.

11. The method of any of numbered embodiments 1-9b, wherein the subjectis between 30 days and 100 years, or 1 and 5, 3 and 18, 18 and 50, 50and 60 or 60 and 80 years of age.

12. The method of any of numbered embodiments 1-9b, wherein the subjectmore than 30 days of age.

13. The method of any of numbered embodiments above, wherein the subjectis immune-compromised, for example, the subject has a hereditary oracquired or induced immune deficiency, or compromised organ function,for example, compromised hepatic or renal function.

13a. The method of any of numbered embodiments above, wherein the siteirradiated comprises skin.

13b. The method of any of numbered embodiments above, wherein the siteirradiated is disposed in whole or part on the arm, leg, torso,genitals, back, neck, head, face, hand, or foot.

13c The method of any of numbered embodiments above, wherein the siteirradiated is disposed in whole or part in a natural orifice, forexample, in the nose, sinus, urethra, ear canal, male or female genitaltract, nasal passage, mouth, throat, upper GI tract and rectum.

13d. The method of any of numbered embodiments above, wherein the siteirradiated comprises entry point of a medical device, for example, thepoint of entry of a conduit, catheter, PIC line, Hickman catheter.

13e. The method of any of numbered embodiments above, wherein the siteirradiated comprises entry point of a conductor, for example, from apower source, for example, the power source for an LVT assist device.

13f. The method of any of numbered embodiments above, wherein the siteirradiated comprises entry point of a conductor or conduit to animplanted medical device, for example, a stent, for example, a biliarystent.

14. The method of any of numbered embodiments 1-13e, wherein the lighthas a wavelength between 380 nm and 500 nm.

14a. The method of any of numbered embodiments 1-13e, wherein the lighthas a wavelength between 390 nm and 430 nm.

14b. The method of any of numbered embodiments 1-13e, wherein the lighthas a wavelength between 395 nm and 415 nm.

14c. The method of any of numbered embodiments 1-13e, wherein the lighthas a wavelength between: 380 nm and 415 nm.

15. The method of any of numbered embodiments 1-13e, wherein the lighthas a wavelength 405 nm+/−10 nm.

16. The method of any of numbered embodiments 1-13e, wherein the lighthas a wavelength 405 nm+/−20 nm.

17. The method of any of numbered embodiments 1-13e, wherein the lighthas a wavelength 405 nm.

18. The method of any of numbered embodiments above, wherein the lightis provided at between 0.25 and 25 milliWatts/cm².

18b. The method of any of numbered embodiments 1-17, wherein the lightis provided at between 1 and 15 milliWatts/cm².

18c. The method of any of numbered embodiments above, wherein the lightis provided at between 5 and 10 milliWatts/cm².

19. The method of any of numbered embodiments 1-17, wherein the light isprovided at 470+/−10.

19. The method of any of numbered embodiments 1-17, wherein the light isprovided at 470+/−20.

20. The method of any of numbered embodiments 1-17, wherein the light isprovided at 5-10 mW/cm².

20a. The method of any of numbered embodiments 1-17, wherein the lightis provided at 5.5-8.33 mW/cm².

20b. The method of any of numbered embodiments 1-20a, wherein thesubject has an acute infection, for example, an acute MRSA, MSSA, or S.epidermis infection and the light is provided at 5.5-8.33 mW/cm².

20c. The method of any of numbered embodiments 1-20a, wherein thesubject has a chronic infection, for example, a chronic infection or achronic antibiotic infection, a VRE, KPC, or NDM1, and the light isprovided at 5-10 mW/cm², for example, 8.33 mW/cm².

21. The method of any of numbered embodiments above, wherein the lightis provided for a time sufficient to prevent the infection of a subjectby a pathogen.

22. The method of any of numbered embodiments above, wherein the lightis provided for a time sufficient reduce the level of a pathogen in asubject.

23. The method of any of numbered embodiments above, wherein the lightis provided for a time sufficient reduce the level of viable pathogen atthe site of irradiation by 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or100 fold.

24. The method of any of numbered embodiments 1-23, wherein the light isprovided for at least 6, 24, 72, or 168 hours.

25. The method of any of numbered embodiments 1-23, wherein the light isprovided for 6 to 168; 12 to 120; or 24 to 72 hours.

26. The method of any of numbered embodiments above, wherein the lightis provided at a total fluence sufficient 240 J/cm2 a pathogen in asubject.

27. The method of any of numbered embodiments 1-25, wherein the light isprovided at a total fluence of at least 60, 240, 6,480, or 15,120 J/cm².

28. The method of any of numbered embodiments 1-25, wherein the light isprovided at a total fluence of 60 to 15,120; 120 to 10,800; or 240 to6,480 J/cm².

29. The method of any of numbered embodiments 1-25, wherein the light isprovided at a total fluence of 60; 240; 6,480; or 15,210 J/cm².

30. The method of any of numbered embodiments above, wherein the lightprovided is sufficient to kill the pathogen but does not result indamage to normal surrounding healthy tissue, such as fibroblasts,keratinocytes, nerves and blood vessels.

31. The method of any of numbered embodiments above, wherein the levelof pathogen is reduced sufficiently such that there is at least 99.0% or99.9% reduction in colony forming units/milliliter (cfu/ml), forexample, at the site of irradiation.

31a. The method of any of numbered embodiments above, wherein the levelof pathogen is reduced sufficiently to confer antibiotic sensitivity.

32. The method of any of numbered embodiments above, wherein the levelof the pathogen in the irradiated tissue is reduced.

33. The method of any of numbered embodiments above, wherein thesystemic or circulatory level of the pathogen is reduced.

34. The method of any of numbered embodiments 1-33, wherein 0.1 to2000.0; 0.25 to 1000.0; 0.5 to 100.0; and 1.0 to 50.0, cm² of thesurface of the subject is irradiated.

35. The method of any of numbered embodiments 1-33, wherein the surfaceirradiated comprises: 0.1, 1.0, 100.0, or 2000.0 cm² of any cutaneousand mucutaneous surface.

36. The method of any of numbered embodiments above, wherein the surfaceirradiated comprises: a wound, a burn, an ulcer, rash, surgicalincision, cut, catheter, bone, cast, orthopedic implant, or bandagedressing.

37. The method of any of numbered embodiments above, wherein the surfaceirradiated comprises a diabetic ulcer, a pressure ulcer, a decubitusulcer, or a venous stasis ulcer.

38. The method of any of numbered embodiments above, wherein theirradiation is administered in a health care facility, for example, ahospital, clinic, or physician's office.

39. The method of any of numbered embodiments 1-37, wherein theirradiation is administered at a place other than a health carefacility, for example, a hospital, clinic, or physician's office, forexample, the irradiation is administered after discharge or exit from ahealth care facility, for example, a hospital, clinic, or physician'soffice.

40. The method of any of numbered embodiments above, wherein theirradiation is initiated in a health care facility, for example, ahospital, clinic, or physician's office.

41. The method of any of numbered embodiments above, wherein theirradiation is initiated at a place other than a health care facility,for example, a hospital, clinic, or physician's office, for example, theirradiation is administered after discharge or exit from a health carefacility, for example, a hospital, clinic, or physician's office.

42. The method of any of numbered embodiments 1-40, wherein theirradiation is initiated in a health care facility, for example, ahospital, clinic, or physician's office and is continued at a placeother than a health care facility, for example, a hospital, clinic, orphysician's office.

43. The method of any of numbered embodiments above, wherein theirradiation is provided as a single treatment, for example, without aperiod where the irradiation ceases.

44. The method of any of numbered embodiments 1-42 wherein theirradiation is provided as a plurality of treatments, for example, theirradiation is initiated and continues for a time, is halted, and isinitiated a second time.

45. The method of any of numbered embodiments 1-42, wherein theirradiation is initiated in a health care facility, for example, ahospital, clinic, or physician's office and is continued for at least 6hours, 1 day, 7 days, or 30 days in the health care facility.

46. The method of any of numbered embodiments 1-42, wherein theirradiation is continued or reinitiated at a place other than the healthcare facility, and, for example, is continued for at least 6 hours, 1day, 7 days, or 30 days at the place other than the healthcare facility.

46a. The method of any of numbered embodiments above, wherein theirradiation is provided by a wearable device.

46b. The method of any of numbered embodiments above, wherein theirradiation is provided by a device weighing less than 15, 10, 5, or 2kilograms.

46c. The method of any of numbered embodiments above, wherein theirradiation is provided by a device comprising a power source, forexample, a wearable power source.

46d. The method of any of numbered embodiments above, wherein theirradiation is provided by a device comprising a battery.

46e. The method of any of numbered embodiments above, wherein theirradiation is provided by a device described herein, for example, inany of numbered embodiments above.

46f. The method of any of numbered embodiments above, wherein the lightis delivered at a radiance that does not deplete O₂ in the pathogen.

46 g. The method of any of numbered embodiments above, wherein the lightis delivered at a radiance that does not bleach a chromophore, forexample, an endogenous chromophore, in the pathogen.

46gi. The method of any of numbered embodiments above, wherein a lightrelated parameter, for example, wavelength, intensity, duration, orcycle can be varied (the alternation of periods of irradiation with anintervening period in which irradiation is not provided, can be variedover area and or time).

46gii. The method of any of numbered embodiments above, wherein lightrelated parameter can be provided at a first value at a first location,for example, a location with relatively more healing, and a second valueat a second location, for example, a location with relatively lesshealing.

46giii. The method of any of numbered embodiments above, wherein thelight is delivered at a first intensity for a first period of time andat a second intensity for second period of time.

46h. The method of any of numbered embodiments above, wherein the lightis delivered at a first intensity to a first site on the subject and ata second intensity at a second site on the subject.

46i. The method of any of numbered embodiments above, wherein the lightis delivered at a first wavelength for a first period of time and at asecond wavelength for second period of time.

46j. The method of numbered embodiment above, wherein the light at thefirst wavelength is optimized for killing a pathogen, for example, bluelight, for example, light having a wavelength of between 390 nm and 420nm, and the light at the second wavelength is optimized for promotingwound healing, for example, red or infrared light, for example, lighthaving a wavelength between 600 nm and 700 nm, for example, light havinga wavelength between 700 nm and 1000 nm.

46k. The method of numbered embodiment above, wherein the first periodof time occurs before the second period of time.

46l. The method of any of numbered embodiments above, wherein the lightis delivered at a first wavelength to a first site on the subject and isdelivered at a second wavelength to a second site on the subject.

46m. The method of numbered embodiment above, wherein the first sitecomprises a first injury or lesion and the second site comprises asecond injury or lesion.

46n. The method of numbered embodiment above, wherein the first sitecomprises a burn and the second site comprises a burn.

46o. The method of numbered embodiment above, wherein the burn at thefirst site comprises burn having a different severity than the burn atthe second site.

46p. The method of numbered embodiment above, wherein the first sitecomprises a third or fourth degree burn.

46q. The method of numbered embodiment above, wherein the second sitecomprises a first or second degree burn.

46r. The method of any of numbered embodiments above, wherein the firstsite is irradiated with light of wavelength of less than 400 nm, forexample, between, 280 and 315 nm (UV-B) or 315 nm and 400 nm (UV-A).

46s. The method of any of numbered embodiments above, wherein the secondsite is irradiated with light of wavelength between, 390 nm and 420 nm,for example, 405 nm.

46t. The method of any of numbered embodiments above, wherein the methodincludes a period or pulse of irradiation, an intervening period whenirradiation is not provided, and a subsequent period or pulse ofirradiation.

46u. The method of numbered embodiment above, wherein the interveningperiod is sufficient in duration to allow an increase in O₂ in thepathogen, as compared to what is present at the beginning of theintervening period.

46i. The method of any of numbered embodiments above, whereinirradiation is provided as a plurality of periods or pulses wherein thepulses are separated by intervening periods when irradiation is notprovided, for example, darkness.

46ii. The method of any of numbered embodiments above, furthercomprising providing a plurality of periods or pulses of irradiation ofat least 0.1, 3,600, or 86,400 seconds each, separated by a interveningperiods of at least 0.1, 3,600, or 86,400 seconds each when irradiationis not provided.

46iii. The method of any of numbered embodiments above, wherein eachpulse of the plurality is of equal duration.

46iv. The method of any of numbered embodiments above, wherein a firstpulse and a second pulse of the plurality are of different duration.

46v. The method of any of numbered embodiments above, wherein eachintervening period is of equal duration.

46vi. The method of any of numbered embodiments above, wherein a firstintervening period and a second intervening period are of differentduration.

46vii. The method of any of numbered embodiments above, wherein thedevice is configured such that ambient light does not reach the surfacecovered by the area, for example, such that the surface is in darknesswhen the irradiation is not provided.

46viii. The method of any of numbered embodiments 1-46vii, wherein atleast 1, 100,000, 1,000,000, or 1,000,000,000 pulses of irradiation areprovided.

46ix. The method of any of numbered embodiments 1-46vii, whereinirradiation is provided at 3600, 30, 15, 5 or 1 cycle(s) per hour,wherein a cycle is a period or pulse of irradiation and interveningperiod.

46x. The method of any of numbered embodiments 1-46vii, whereinirradiation is provided at 3600 to 1; 30 to 5; or 20 to 10 cycle(s) perhour, wherein a cycle is a period or pulse of irradiation andintervening period.

46xi. The method of any of numbered embodiments 1-46vii, wherein aperiod of irradiation (for example, over a 24-hour period) delivers0.00025 (0.25 mW*1 sec), 1, 10, 100, 1000, or 2,160 (25 mW*86,400 sec)J/cm².

46xii. The method of any of numbered embodiments above, wherein a periodof irradiation (for example, over a 24-hour period) delivers 0.00025 to2,160; 1 to 1,000; or 100 to 500 J/cm²

46xiii. The method of any of numbered embodiments above, wherein aperiod of irradiation delivers sufficient light that bacteria cell deathoccurs, for example, 99.0% or 99.9% Log reduction in CFU/ml.

46xiv. The method of any of numbered embodiments above, wherein a periodof irradiation is sufficiently limited that it does not result in damageto surrounding normal healthy tissue.

46xv. The method of any of numbered embodiments above, whereinintervening period is of sufficient duration that:

i) there is regeneration of chromophores that absorb at the irradiatedfrequency;

ii) O₂ in the wound increases, for example, increases sufficiently thatthe photodynamic reaction can occur; or

iii) diffusion of O₂ from surrounding tissues occurs.

46xvi. The method of any of numbered embodiments above, wherein theirradiation is pulsed and the symmetry remains constant throughout thetreatment.

46xvii. The method of any of numbered embodiments above, wherein theirradiation is pulsed and the symmetry value changes over time.

46xvii. The method of any of numbered embodiments above, wherein theirradiation is pulsed and the symmetry value increases over time.

46xix. The method of any of numbered embodiments above, wherein theirradiation is pulsed and the symmetry value decreases over time.

46xx. The method of any of numbered embodiments above, wherein theirradiation is pulsed and the symmetry value changes or is changed overtime in response to the condition of the subject.

46xxi. The method of any of numbered embodiments above, wherein theirradiation is pulsed and the wave form of the irradiation period isstep or square wave, a saw-tooth wave form, a triangle wave form, adiscrete piece wise wave form, or a sinusoidal wave form.

46v. The method of numbered embodiment above, wherein the interveningperiod is sufficient to allow an increase in a chromophore in thepathogen, as compared to what is present at the beginning of theintervening period.

46w. The method of numbered embodiment 46v, wherein the interveningperiod is 0.00167 to 60, 1 to 20, for example, 1, 2, 3, 4, or 5, minutesin duration.

46wi. The method of numbered embodiment 46v, wherein the interveningperiod is at least 1, 2, 3 4, 5, 6, 7, 8, 9 or 10 hours in duration.

46x. The method of any of numbered embodiments above, whereinirradiation is cycled between periods of irradiation and interveningperiods for at least 0.0000277, 1, 10, 24, 48, 72, or 96 hours.

47. The method of any of numbered embodiments above, wherein thepathogen comprises a bacterium, fungus, protozoan, spore, virus,helminthes (for example, a. Nematode, flatworm, roundworm), or anextoparasite.

48. The method of any of numbered embodiments above, wherein thepathogen comprises a bacterium from Table 3, a fungus, or a protozoanfrom Table2.

49. The method of any of numbered embodiments above, wherein thepathogen comprises a drug resistant pathogen.

50. The method of any of numbered embodiments above, wherein thepathogen comprises a bacterium and is resistant to a drug from Table 3or 4.

51a. The method of any of numbered embodiments above, wherein thepathogen comprises Acinetobacter baumannii, for example,carbapenem-resistant Acinetobacter baumannii.

51b. The method of any of numbered embodiments above, wherein thepathogen comprises Pseudomonas aeruginosa, for example,carbapenem-resistant Pseudomonas aeruginosa.

51c. The method of any of numbered embodiments above, wherein thepathogen comprises Enterobacteriaceae, for example, carbapenem-resistantor ESBL-producing Enterobacteriaceae.

51d. The method of any of numbered embodiments above, wherein thepathogen comprises Enterococcus faecium, for example,vancomycin-resistant Enterococcus faecium.

51e. The method of any of numbered embodiments above, wherein thepathogen comprises Staphylococcus aureus, for example,methicillin-resistant, vancomycin-intermediate and resistantStaphylococcus aureus.

51f. The method of any of numbered embodiments above, wherein thepathogen comprises Helicobacter pylori, for example,clarithromycin-resistant Helicobacter pylori.

51 g. The method of any of numbered embodiments above, wherein thepathogen comprises Campylobacter spp, for example,fluoroquinolone-resistant Campylobacter spp.

51h. The method of any of numbered embodiments above, wherein thepathogen comprises Salmonellae, for example, fluoroquinolone-resistantSalmonellae.

51i. The method of any of numbered embodiments above, wherein thepathogen comprises Neisseria gonorrhoeae, for example,cephalosporin-resistant or fluoroquinolone-resistant Neisseriagonorrhoeae.

51j. The method of any of numbered embodiments above, wherein thepathogen comprises Streptococcus pneumoniae, for example,penicillin-non-susceptible Streptococcus pneumoniae.

51k. The method of any of numbered embodiments above, wherein thepathogen comprises Haemophilus influenzae, for example,ampicillin-resistant Haemophilus influenzae.

51l. The method of any of numbered embodiments above, wherein thepathogen comprises Shigella spp., for example, fluoroquinolone-resistantShigella spp.

51m. The method of any of numbered embodiments above, wherein thepathogen comprises a parasitic infection, and the parasite obtains hemefrom the subject.

51n. The method of any of numbered embodiments above, wherein thepathogen comprises Trypanosoma cruzi.

51o. The method of any of numbered embodiments above, wherein thepathogen comprises taenia solium.

51p. The method of any of numbered embodiments above, wherein thepathogen comprises toxocara.

52. The method of any of numbered embodiments above, wherein thepathogen comprises Staphylococcus aureus (MRSA methicillin RSA and MSSAmethycilllin) and Staph. epidermidis (coagulase-negative Staph) and isresistant to methicillin, vancomycin, or doxycycline.

53. The method of any of numbered embodiments above, wherein thepathogen is a pathogen from Table 3 and is resistant to a drug fromTable 3 or 4.

55. The method of any of numbered embodiments above, wherein the subjectcomprises a second, third, fourth, fifth, sixth or seventh pathogen.

56. The method of any of numbered embodiments above, wherein the subjecthas a burn and the burn is infected with, or at risk for infection with,the pathogen.

57. The method of any of numbered embodiments above, wherein the subjecthas an injury to the skin or mucosa resulting in a partial- orfull-thickness wound.

59. The method of any of numbered embodiments above, wherein the subjecthas not been treated with an exogenous compound, for example, a dye orphotosensitizer, for example, one selected from Table 1, for example,photofrin or ALA.

59. The method of any of numbered embodiments 1-57, wherein the subjecthas been treated with an exogenous compound, for example, a dye orphotosensitizer, for example, one selected from Table 1, for example,photofrin or ALA.

60. The method of any of numbered embodiments above, wherein, at a timeduring irradiation, for example, at initiation, or for the entire courseof irradiation, the irradiated tissue does not comprise an exogenouscompound which absorbs light at 380 nm to 500 nm, for example, anexogenous compound, for example, a dye or photosensitizer, for example,photofrin or ALA.

61. The method of any of numbered embodiments above, wherein a secondtherapeutic agent is provided, for example, administered, to thesubject.

62. The method of numbered embodiment above, wherein the secondtherapeutic agent comprises an antibiotic, for example, Ampicillin,Methicillin, or Vancomycin.

63. The method of numbered embodiment above, wherein the antibioticcomprises an antibiotic from Table 3 or 4.

64. The method of any of numbered embodiments above, wherein the secondtherapeutic agent is provided systemically, for example, by intravascular, for example, intravenous administration.

65. The method of any of numbered embodiments above, wherein treatmentwith the second therapeutic agent is initiated prior to initiation ofirradiation, at the same time as initiation of irradiation, afterinitiation of irradiation, during the course of irradiation, or afterthe course of irradiation.

66. The method of any of numbered embodiments 1-65, wherein irradiationis initiated prior to initiation of the provision of the secondtherapeutic agent, at the same time as initiation of provision of thesecond therapeutic agent, after initiation of provision of the secondtherapeutic agent, during the course of provision of the secondtherapeutic agent, or after the provision of the second therapeuticagent.

67. The method of any of numbered embodiments above, wherein the secondtherapeutic agent comprises an agent from Table 3, 4 or 0.5.

67a. The method of any of numbered embodiments above, comprising theapplication of negative pressure to the wound bed.

67b. The method of numbered embodiment 67a, wherein the negativepressure is constant throughout the use of the device or throughout aportion of the time the device is contacted with the subject.

67c. The method of any of numbered embodiments 67a-67b, whereindifferent pressures, for example, at different times of the day, atdifferent stages of treatment or healing, or with different wavelengthsof light being applied.

67d. The method of any of numbered embodiments 67a-67c, wherein a firstlevel of negative pressure is applied at a first point of a preselectedperiod, for example, a 24 hour period, and a second level of negativepressure is applied at a second point of the preselected period.

67e. The method of any of numbered embodiments 67a-67c, wherein a firstlevel of negative pressure is applied at a first stage of healing ortreatment, and a second level of negative pressure is applied at asecond stage of healing or treatment.

67f. The method of any of numbered embodiments 67a-67c, wherein a firstlevel of negative pressure is applied during irradiation at a firstwavelength, and a second level of negative pressure is applied duringirradiation with a second wavelength.

Method of Treating a Subject Having a Burn

68. A method of treating a subject having a burn, the method comprising:

irradiating the subject with light having a wavelength between 380 nmand 500 nm at 0.25 to 25 milliWatts/cm²,

wherein the irradiation is for a time sufficient to prevent infection ofthe subject by a pathogen reducing the level of a pathogen (for example,in the burn or systemically), or reducing or otherwise ameliorating anunwanted manifestation of infection by a pathogen (for example, in theburn or systemically) in a subject.

69. The method of numbered embodiment 68, wherein the subject at riskfor a pathogen infection (for example, in the burn or systemically).

70. The method of numbered embodiment above, further comprisingpreventing the infection of the subject (for example, in the burn orsystemically), by the pathogen.

71. The method of numbered embodiment above, further comprising reducingthe level of pathogen (for example, in the burn or systemically).

72. The method of numbered embodiment above, further comprising reducingor otherwise ameliorating an unwanted manifestation of infection by apathogen (for example, in the burn or systemically).

73. The method of numbered embodiment above, further comprising reducingtoxins released by or created by a pathogen or making the pathogen moresensitive to an antimicrobial agent.

74. The method of any of numbered embodiments above, wherein the subjectis less than 1, 2, 5, 10, 18, 30, 50, 60 75 or 100 years of age.

75. The method of any of numbered embodiments above, wherein the subjectis between 30 days and 100 years, or 1 and 5, 3 and 18, 18 and 50, 50and 60, or 60 and 80 years of age.

76. The method of any of numbered embodiments above, wherein the subjectmore than 30 days of age.

77. The method of any of numbered embodiments above, wherein the subjecthas a burn wound beyond 1^(st) degree burn and greater than 10% totalbody surface area (TBSA).

78. The method of any of numbered embodiments above, wherein the burncomprises a first-, second- or third-degree burn.

79. The method of any of numbered embodiments above, wherein the burncovers more than 1%, 5%, 10%, 25% or 50% of the subject's body.

80. The method of any of numbered embodiments above, wherein the burncovers from: 1% to 100%; from 2% to 90%; 5% to 80%; or 10% to 50% of thesubject's body.

81. The method of any of numbered embodiments above, wherein the burncomprises the subject's arm, leg, torso, face, back, genitals, orextremities (fingers, toes).

82. The method of any of numbered embodiments above, wherein the burn isa thermal burn.

83. The method of any of numbered embodiments above, wherein the burn isa fire/flame burn, a scald, a burn from contact with a hot object, anelectrical burn, or chemical burn.

84. The method of any of numbered embodiments above, wherein irradiationis initiated within 0, 24, 72, or 168 hours of infliction of the burn.

85. The method of any of numbered embodiments above, wherein irradiationis initiated more than 0, 4, 72, or 168 hours after infliction of theburn.

87. The method of any of numbered embodiments above, wherein the lighthas a wavelength between: 380 nm and 500 nm; 390 nm and 430 nm; and 395nm and 415 nm.

88. The method of any of numbered embodiments above, wherein the lighthas a wavelength 405+/−10.

88. The method of any of numbered embodiments above, wherein the lighthas a wavelength 405+/−20.

89. The method of any of numbered embodiments above, wherein the lighthas a wavelength 405 nm.

90. The method of any of numbered embodiments above, wherein the lightis provided at between 0.25 and 25 milliWatts/cm².

91. The method of any of numbered embodiments above, wherein the lightis provided at 6+/−3 milliWatts/cm².

92. The method of any of numbered embodiments above, wherein the lightis provided at 5.5 mW/cm².

93. The method of any of numbered embodiments above, wherein the lightis provided for a time sufficient to prevent the infection of a subjectby a pathogen.

94. The method of any of numbered embodiments above, wherein the lightis provided for a time sufficient reduce the level of a pathogen in asubject.

95. The method of any of numbered embodiments above, wherein the lightis provided for a time sufficient kill or neutralize a pathogen in asubject.

96. The method of any of numbered embodiments above, wherein the lightis provided for at least 6, 24, 72, or 168 hours.

97. The method of any of numbered embodiments above, wherein the lightis provided for 6 to 168; 12 to 120; or 24 to 72 hours.

98. The method of any of numbered embodiments 68-97, wherein the lightis provided at a total fluence sufficient 90 J/cm² a pathogen in asubject.

99. The method of any of numbered embodiments 68-97, wherein the lightis provided at a total fluence of at least 60, 240, 6,480, or 15,120J/cm².

100. The method of any of numbered embodiments 68-97, wherein the lightis provided at a total fluence of 60 to 15,120; 120 to 880; or 240 to6,480 J/cm².

101. The method of any of numbered embodiments 68-97, wherein the lightis provided at a total fluence of 60, 240, 6,480, or 15,210 J/cm².

102. The method of any of numbered embodiments above, wherein the lightprovided is sufficient to kill bacteria but does not result in damage tohealthy tissue.

103. The method of any of numbered embodiments above, wherein the levelof pathogen is reduced such that there is a 3 log reduction in thenumber of colony forming units (cfu) of pathogens per milliliter (ml)(i.e. cfu/ml).

104. The method of any of numbered embodiments above, wherein the levelof the pathogen in the irradiated tissue is reduced.

105. The method of any of numbered embodiments above, wherein thesystemic or circulatory level of the pathogen is reduced.

106. The method of any of numbered embodiments 68-105, wherein 0.1 to2000; 0.25 to 1000; 0.5 to 100; and 1.0 to 50, cm² of the surface of theburn is irradiated.

107. The method of any of numbered embodiments 68-105, wherein 1 to 100;2 to 90; 5 to 80; and 10 to 50, % of the surface of the burn isirradiated.

109. The method of any of numbered embodiments 68-107, wherein theirradiation is administered in a health care facility, for example, ahospital, clinic, or physician's office.

110. The method of any of numbered embodiments 68-107, wherein theirradiation is administered at a place other than a health carefacility, for example, a hospital, clinic, or physician's office, forexample, the irradiation is administered after discharge or exit from ahealth care facility, for example, a hospital, clinic, or physician'soffice.

111. The method of any of numbered embodiments 68-107, wherein theirradiation is initiated in a health care facility, for example, ahospital, clinic, or physician's office.

112. The method of any of numbered embodiments 68-107, wherein theirradiation is initiated at a place other than a health care facility,for example, a hospital, clinic, or physician's office, for example, theirradiation is administered after discharge or exit from a health carefacility, for example, a hospital, clinic, or physician's office.

113. The method of any of numbered embodiments 68-107, wherein theirradiation is initiated in a health care facility, for example, ahospital, clinic, or physician's office and is continued at a placeother than a health care facility, for example, a hospital, clinic, orphysician's office.

114. The method of any of numbered embodiments above, wherein theirradiation is provided as a single treatment, for example, without aperiod where the irradiation ceases.

115. The method of any of numbered embodiments 68-113, wherein theirradiation is provided as a plurality of treatments, for example, theirradiation is initiated and continues for a time, is halted, and isinitiated a second time.

116. The method of any of numbered embodiments 68-107, wherein theirradiation is initiated in a health care facility, for example, ahospital, clinic, or physician's office and is continued for at least 6hours, 1 day, 7 days, or 30 days in the health care facility.

117. The method of any of numbered embodiments, wherein the irradiationis continued or reinitiated at a place other than the health carefacility, and, for example, is continued for at least 6 hours, 1 day, 7days, or 30 days at the place other than the healthcare facility.

118. The method of any of numbered embodiments above, wherein thepathogen comprises a bacterium, fungus, protozoan, or spore or cyststage of pathogen.

119. The method of any of numbered embodiments above, wherein thepathogen comprises a bacterium from Table 3, a fungus, or a protozoanfrom Table 2.

120. The method of any of numbered embodiments above, wherein thepathogen comprises a drug resistant pathogen.

121. The method of any of numbered embodiments above, wherein thepathogen comprises a bacterium and is resistant to a drug from Table 3or 4.

122. The method of any of numbered embodiments above, wherein thepathogen comprises Acinetobacter baumannii, for example,carbapenem-resistant Acinetobacter baumannii.

123. The method of any of numbered embodiments above, wherein thepathogen comprises Pseudomonas aeruginosa, for example,carbapenem-resistant Pseudomonas aeruginosa.

124. The method of any of numbered embodiments above, wherein thepathogen comprises Enterobacteriaceae, for example, carbapenem-resistantor ESBL-producing Enterobacteriaceae.

125. The method of any of numbered embodiments above, wherein the methodreduces the virulence of the pathogen, reduces the amount of toxinrelease by a pathogen, increases the sensitivity of the pathogen to anantimicrobial agent, or renders the pathogen unable to replicate.

126. The method of any of numbered embodiments above, wherein thesubject comprises a second pathogen.

127. The method of any of numbered embodiments above, wherein thesubject has not been treated with an exogenous compound, for example, adye or photosensitizer.

127b. The method of any of numbered embodiments 1-126, wherein thesubject has been treated with an exogenous compound, for example, a dyeor photosensitizer.

128. The method of any of numbered embodiments above, wherein, at a timeduring irradiation, for example, at initiation, or for the entire courseof irradiation, the irradiated tissue does not comprise an exogenouscompound which absorbs light at 380 nm to 500 nm, for example, anexogenous compound, for example, a dye or photosensitizer, for example,Photofrin or ALA.

129. The method of any of numbered embodiments above, wherein a secondtherapeutic agent is provided, for example, administered, to thesubject.

130. The method of numbered embodiment above, wherein the secondtherapeutic agent comprises an antibiotic, Ampicillin, Methicillin, orVancomycin.

140. The method of numbered embodiment above, wherein the antibioticcomprises an antibiotic from Table 3 or 4.

145. The method of any of numbered embodiments above, wherein the secondtherapeutic agent is provided systemically, for example, by intravascular, for example, intravenous administration.

146. The method of any of numbered embodiments 68-145, wherein treatmentwith the second therapeutic agent is initiated prior to initiation ofirradiation, at the same time as initiation of irradiation, afterinitiation of irradiation, during the course of irradiation, or afterthe course of irradiation.

147. The method of any of numbered embodiments 68-145, whereinirradiation is initiated prior to initiation of the provision of thesecond therapeutic agent, at the same time as initiation of provision ofthe second therapeutic agent, after initiation of provision of thesecond therapeutic agent, during the course of provision of the secondtherapeutic agent, or after the provision of the second therapeuticagent.

148. The method of any of numbered embodiments above, wherein the secondtherapeutic agent comprises an agent from Table 3, 4, or 0.5.

148a. The method of any of numbered embodiments above, furthercomprising administering to the subject and anesthetic, for example, ageneral or local anesthetic.

148b. The method of any of numbered embodiments above, where the siteirradiated is in contact with an aqueous liquid, for example, saline orwater.

148c. The method of any of numbered embodiments above, furthercomprising providing the site irradiated with an aqueous liquid, forexample, saline or water.

148d. The method of any of numbered embodiments 68-148c, comprising theapplication of negative pressure to the wound bed.

148e. The method of numbered embodiment 148d, wherein the negativepressure is constant throughout the use of the device or throughout aportion of the time the device is contacted with the subject.

148f. The method of any of numbered embodiments 148d-148e, whereindifferent pressures, for example, at different times of the day, atdifferent stages of treatment or healing, or with different wavelengthsof light being applied.

148 g. The method of any of numbered embodiments 148d-148e, wherein afirst level of negative pressure is applied at a first point of apreselected period, for example, a 24 hour period, and a second level ofnegative pressure is applied at a second point of the preselectedperiod.

148h. The method of any of numbered embodiments 148d-148e, wherein afirst level of negative pressure is applied at a first stage of healingor treatment, and a second level of negative pressure is applied at asecond stage of healing or treatment.

148i. The method of any of numbered embodiments 148d-148e, wherein afirst level of negative pressure is applied during irradiation at afirst wavelength, and a second level of negative pressure is appliedduring irradiation with a second wavelength.

150. A device for providing light to the surface of a subject, thedevice comprising:

a) an array of a plurality of light emitting modules,

-   -   each module of the plurality being flexibly connected to another        module of the plurality, and    -   each module of the plurality being capable of emitting light,        wherein the array is configured to conform to the surface of the        subject.

151. The device of numbered embodiment 150, further comprising:

b) light or energy source.

152. The device of numbered embodiment above, further comprising:

c) a connector for transmitting current or light from b to a.

153. The device of any of numbered embodiments above, wherein two ormore modules of the plurality are configured so as to be able to emitlight simultaneously.

153a. The device of any of numbered embodiments above, wherein thedevice is configured to allow changing the intensity of light across thewound bed so that some areas receive more light than other areas, forexample, responsive to the degree of wound healing or closure.

153b. The device of any of numbered embodiments above, wherein two ormore modules of the plurality are configured so as be separatelycontrollable, for example, as to intensity.

154. The device of any of numbered embodiments above, wherein one ormore modules of the plurality is configured so as to be able tosimultaneously emit light at more than one wavelength.

154a. The device of any of numbered embodiments above, wherein the arrayof modules is flexible, stretchable, or can be molded to a surface.

155b. The device of any of numbered embodiments above, wherein the arrayof modules can be bent to conform to surface or body part of the subjectand when bent to a conforming shape retains the conforming shape.

155c. The device of any of numbered embodiments above, wherein the arrayof modules can be bent to conform to a surface or body party of thesubject in a plurality of dimensions, for example, in two dimensions.

155. The device of any of numbered embodiments 150-155c, wherein eachmodule of the plurality is configured to provide light having awavelength between 250 nm and 500 nm, and a wavelength between 280 nmand 315 nm.

156. The device of any of numbered embodiments 150-155c, wherein eachmodule of the plurality is configured to provide light at 0.25 to 25milliWatts/cm², for example, at the surface of the subject.

157. The device of any of numbered embodiments 150-155c, wherein eachmodule of the plurality is configured to provide light having awavelength between: 380 nm and 500 nm; 390 nm and 430 nm; and 395 nm and415 nm.

157. The device of any of numbered embodiments 150-155c, wherein eachmodule of the plurality is configured to provide light having awavelength between: 625-690 nm, for example, for wound healing.

158. The device of any of numbered embodiments 150-155c, configured toprovide light having a wavelength of 405 nm+/−10 nm.

158. The device of any of numbered embodiments 150-155c, configured toprovide light having a wavelength of 405 nm+/−20 nm.

159. The device of any of numbered embodiments 150-155c, configured toprovide light having a wavelength 405 nm.

160. The device of any of numbered embodiments 150-155c, wherein eachmodule of the plurality is configured to provide light between 0.25 and25 milliWatts/cm².

161. The device of any of numbered embodiments 150-155c, wherein eachmodule of the plurality is configured to provide light at 6+/−3 mW/cm².

162. The device of any of numbered embodiments 150-155c, wherein eachmodule of the plurality is configured to provide light at 6 mW/cm².

163. The device of any of numbered embodiments above, further comprisingat least 2, 4, 6, 10, 20, 30, 40 or 50 modules.

164. The device of any of numbered embodiments 150-162, furthercomprising no more than 2, 4, 6, 10, 20, 30, 40, 50, 75, 100, 150, 200,or 400 modules.

165. The device of any of numbered embodiments 150-162, furthercomprising 2 to 400; 3 to 200; 4 to 100; 5 to 50; 10 to 40; or 20 to 30,modules.

166. The device of any of numbered embodiments 150-162, wherein modulesof the plurality of modules are present at a density of at least 62,000(5.0 mm hexagon diagonal area=0.00001624 m² and gives a density of61,729), 6,800 (15.0 mm hexagon diagonal area=0.00014614 m² and gives adensity of 6,843), 3,000 (22.5 mm hexagon diagonal area=0.00032882 m²and gives a density of 3,042), 600 (50.0 mm hexagon diagonalarea=0.0016238 m² and gives a density of 616) modules/meter².

167. The device of any of numbered embodiments 150-162, wherein modulesof the plurality of modules are present at a density of no more than500, 3,000, 6,800, 62,000 or modules/meter².

168. The device of any of numbered embodiments 150-162, wherein modulesof the plurality of modules are present at a density of 600 to 62,000;1200 to 15,000; 1700 to 6,800; 2,400 to 3,800 (20 mm); 2,900 (23 mm) to3,200; modules/meter².

168a. The device of any of numbered embodiments 150-162, wherein amodule has a longest apex to apex distance, or a longest dimension of atleast 5, 10, 20, 30, or 50 millimeters.

168b. The device of any of numbered embodiments 150-162, wherein amodule has a longest apex to apex distance, or a longest dimension of nomore than 5, 10, 20, 30, or 50 millimeters.

168c. The device of any of numbered embodiments 150-162, wherein amodule has a longest apex to apex distance, or a longest dimension of2.5-100; 5-50; 10-40; 15-30; or 20-30; millimeters.

168d. The device of any of numbered embodiments 150-162, wherein amodule, for example, a module with a hexagonal perimeter, has a longestapex to apex distance, or a longest dimension of 20-25 millimeters.

168e. The device of any of numbered embodiments 150-162, wherein amodule, for example, a module with a hexagonal perimeter, has a longestapex to apex distance, or a longest dimension of 10-50 millimeters.

168f. The device of any of numbered embodiments 150-162, wherein amodule, for example, a module with a hexagonal perimeter, has a longestapex to apex distance, or a longest dimension of 22.5 millimeters.

168 g. The device of any of numbered embodiments 150-162, wherein themodule, for example, a hexagonal module, has a side of 2.50 mm to 25.00mm, for example, 11.25 mm.

169. The device of any of numbered embodiments above, wherein eachmodule of the plurality of modules comprises a light emitting device.

170. The device of numbered embodiment 169, wherein the light emittingdevice comprises a light emitting diode, an optical fiber, laser diodes,organic light emitting diodes (OLEDs) or quantum dots.

171. The device of any of numbered embodiments above, wherein the lightemitting device is configured to emit a single wavelength.

172. The device of any of numbered embodiments 150-171, wherein a modulecomprises a first light emitting device which emits light at a firstwavelength and a second light emitting device that emits light at asecond wavelength.

173. The device of any of numbered embodiments above, wherein eachmodule of the plurality comprises a polygonal perimeter.

174. The device of any of numbered embodiments above, wherein eachmodule of the plurality comprises a hexagonal perimeter.

175. The device of any of numbered embodiments above, wherein a modulecomprises a layer configured to receive light, for example, from anedge, which is internally reflective, and comprises one or a pluralityof ports for emission of light.

176. The device of any of numbered embodiments above, further comprisinga diffusing member, which results in a substantially uniform level ofirradiation, for example, as measured by mW/cm².

177. The device of any of numbered embodiments above, wherein the moduleis configured such that, and the level of light delivered is such that,sufficient heat to cause thermal injury, to inhibit kearatinocytegrowth, to inhibit fibroblast growth, or to inhibit wound healing, isnot transferred to the subject.

178. The device of any of numbered embodiments above, wherein theplurality of modules is provided as an array.

179. The device of any of numbered embodiments 150-178, wherein thearray comprises at least 2, 4, 6, 10, 20, 30, 40 or 50 modules.

180. The device of any of numbered embodiments 150-178, wherein thearray comprises no more than 2, 4, 6, 10, 20, 30, 40, 50, 75, 100, 150,200, or 400 modules.

181. The device of any of numbered embodiments 150-178, wherein thearray comprises 2 to 400; 3 to 200; 4 to 100; 5 to 50; 10 to 40; or 20to 30, modules.

182. The device of any of numbered embodiments 150-178, wherein modulesare present in the array at a density of at least 250, 3,000, 6,800,100,000 modules/meter².

183. The device of any of numbered embodiments 150-178, wherein modulesof the plurality of modules are present at a density of no more than500, 3,000, 6,800, 62,000 or modules/meter².

184. The device of any of numbered embodiments 150-178, wherein modulesof the plurality of modules are present at a density of 600 to 62,000;1200 to 15,000; 1700 to 6,800; 2,400 to 3,800 (20 mm); 2,900 (23 mm) to3,200; modules/meter².

185. The device of any of numbered embodiments above, wherein a majorperimeter side of a first module, for example, a hexagonal module, and amajor perimeter side of a second module, for example, a hexagonalmodule, are spaced apart, for example, spaced apart so as to optimize 1)flexibility and 2) maximize uniformity of the light filed.

185a. The device of any of numbered embodiments above, wherein thedevice, for example, the module array of the device, is configured suchthat the surface of the subject under a plurality of modules, or underthe module array, receives a uniform level of irradiation, for example,the level of irradiation does not differ by more than 1%, 5%, 10%, 20%,25%, or 30%.

185b. The device of any of numbered embodiments above, wherein thedevice, for example, the module array of the device, is configured suchthat it has a bend radius of 5 mm.

185c. The device of any of numbered embodiments above, wherein thedevice, the module array of the device, is configured such that thearray can be applied to a site on the surface of the subject with thefaces of the modules that against the subject lie flat against thesubject.

185d. The device of numbered embodiment above, wherein the sitecomprises an arm, a leg, the neck, the torso, or the head, and the arraycovers at least 25%, 50%, 75%, or 100% of the circumference of thesubject.

186. The device of any of numbered embodiments above, wherein thespacing between a major perimeter side of a first module and a majorperimeter side of a second module is: less than 2%, 5%, 10% or 15% ofthe longest apex to apex dimension of a module.

187. The device of any of numbered embodiments above, wherein thespacing between a major perimeter side of a first module and a majorperimeter side of a second module is:

less than 2% to 15%; 3% to 12%; or 4% to 8% of the longest apex to apexdimension of a module.

188. The device of any of numbered embodiments 150-186, wherein thespacing between a major perimeter side of a first module and a majorperimeter side of a second module is:

less than 0.75 mm, 1.5 mm, 3.0 mm, or 7.5 mm.

189. The device of any of numbered embodiments 150-186, wherein thespacing between a major perimeter side of a first module and a majorperimeter side of a second module is:

less than 0.75 mm to 7.5 mm; 1.0 mm to 3.0 mm; or 1.5 mm to 2.0 mm.

190. The device of any of numbered embodiments 150-186, wherein thespacing between a major perimeter side of a first module and a majorperimeter side of a second module is:

0.75 mm, 1.5 mm, 3.0 mm, or 7.5 mm.

191. The device of any of numbered embodiments 150-186, wherein thespacing between a major perimeter side of a first module and a majorperimeter side of a second module is:

1.6+/−10% millimeters.

192. The device of any of numbered embodiments 150-186, wherein thespacing between a major perimeter side of a first module and a majorperimeter side of a second module is:

1.6 mm.

193. The device of numbered embodiment above, wherein a module has aproximal face that faces the surface of the subject and a distal facethat faces way from the surface of the subject.

193a. The device of any of numbered embodiments above, wherein the arraycomprises:

a backing member, for example, flexible material, for example, a layerof foam, which covers or contacts a plurality of modules of the array;and

b) optionally, an adhesive member disposed between the backing memberand a module.

193c. The device of numbered embodiment above, wherein the backingmember is adjacent the distal face of a module.

193d. The device of any of numbered embodiments above, wherein the arraycomprises a diffusion member, for example, a translucent member whichallows the passage of light from a plurality of modules but results in amore uniform field of irradiation than would be seen in its absence.

193e. The device of numbered embodiment above, wherein the diffusionmember is adjacent the proximal face of a module.

193f. The device of any of numbered embodiments above, wherein the arraycomprises a reflective member or layer configured so as to reflect ortransmit light in a way to homogenize the light uniformity or togenerate specific Bi-directional Reflection Distribution functions(BDRF) that can limit the light profile to specific angular andradiometric light output.

194. The device of any of numbered embodiments above, wherein modulesare present in the array having an X axis and a Y axis and the array isat least 1, 3, 10, or 100 modules in length along the X axis and atleast 1, 3, 10, or 100 modules in length along the Y axis.

194a. The device of numbered embodiment 194, wherein X is 3, or more,and Y is 12 or more.

195. The device of any of numbered embodiments 1-194a, wherein modulesare present in the array having an X axis and a Y axis and the array isno more than 5 mm, 10 mm, 25 mm, or 50 mm modules in length along the Xaxis and no more than 5 mm, 10 mm, 25 mm, or 100 mm modules in lengthalong the Y axis.

196. The device of any of numbered embodiments 1-194a, wherein modulesare present in the array having an X axis and a Y axis and the array is5 mm to 50 mm; 10 mm to 40 mm; 15 mm to 30 mm; or 20 mm to 25 mm,modules in length along the X axis and is 5 mm to 50 mm; 10 mm to 40 mm;15 mm to 30 mm; or 20 mm to 25 mm, modules in length along the Y axis.

197. The device of any of numbered embodiments 1-194a, wherein modulesare present in the array having an X axis and a Y axis and the array isat least 0.5, 1.0, 2.5, or 5.0 centimeters in length along the X axisand at least 0.5, 1.0, 2.5, or 5.0 centimeters in length along the Yaxis.

198. The device of any of numbered embodiments 1-194a, wherein modulesare present in the array having an X axis and a Y axis and the array isno more than 0.5, 1.0, 2.5, or 5.0 centimeters in length along the Xaxis and no more than 0.5, 1.0, 2.5, or 5.0 centimeters in length alongthe Y axis.

199. The device of any of numbered embodiments 1-194a, wherein modulesare present in the array having an X axis and a Y axis and the array is0.5 to 5.0; 1.0 to 4.0; 1.5 to 3.0; or 2.0 to 2.5, centimeters in lengthalong the X axis and is 0.5 to 5.0; 1.0 to 4.0; 1.5 to 3.0; or 2.0 to2.5, centimeters in length along the Y axis.

200. The device of any of numbered embodiments above, wherein the arrayis configured to cover the head, neck, back, torso, an arm, a leg,genitals, a finger, or toe.

201. The device of any of numbered embodiments above, further comprisingan array of modules configured for engagement with a second array ofmodules.

202. The device of any of numbered embodiments above, further comprisingan array of modules engaged with a second array of modules.

202. The device of any of numbered embodiments above, further comprisingan array of modules configures so as to be coupled with a second arrayof modules.

203. The device of any of numbered embodiments above, further comprisinga sensor.

204. The device of any of numbered embodiments above, wherein the sensorcomprises a temperature sensor, for example, a thermistor.

205. The device of any of numbered embodiments above, wherein the sensorcomprises a pH sensor.

206. The device of any of numbered embodiments above, wherein the sensorcomprises an O₂ sensor, for example, a sensor which allows evaluation ofoxyhemoglobin/deoxyhemoglobin levels.

207. The device of any of numbered embodiments above, wherein the sensorcomprises a pressure sensor.

208. The device of any of numbered embodiments above, wherein the sensorcomprises a turbidity sensor.

209. The device of any of numbered embodiments above, wherein the sensorcomprises a fluid sensor.

210. The device of any of numbered embodiments above, further comprisingone, two, three, four, five or all of: a temperature sensor, a pHsensor, an O₂ sensor, a pressure sensor, a turbidity sensor, or a fluidsensor.

211. The device of any of numbered embodiments above, wherein a sensoris connected, for example, wirelessly connected, with a processor orcomputer.

212. The device of any of numbered embodiment above, responsive to asignal from the sensor, the device, or a processor or computer connectedthereto, provides a signal, for example, an alert, to another device ora person, for example, the subject or a caregiver.

213. The device of any of numbered embodiment above, responsive to asignal from the sensor, the device, or a processor or computer connectedthereto, alters an activity or property of the device.

214. The device of numbered embodiment above, wherein the device isresponsive to a signal from the sensor, or a processor or computerconnected thereto, to alter a level of irradiation.

215. The device of any of numbered embodiments above, further comprisingan element for positioning the device or the array against the subject,for example, an inflatable device.

216. The device of numbered embodiment above, wherein the device isresponsive to a signal from the sensor, or a processor or computerconnected thereto, to alter a parameter, for example, pressure, of theelement for positioning.

216a. The device of any of numbered embodiments above, wherein theirradiation is provided by a wearable device.

216b. The device of any of numbered embodiments above, wherein theirradiation is provided by a device weighing less than 15, 10, 5, or 2kilograms.

216c. The device of any of numbered embodiments above, wherein theirradiation is provided by a device comprising a power source, forexample, a wearable power source.

216d. The device of any of numbered embodiments above, wherein theirradiation is provided by a device comprising a battery.

216e. The device of any of numbered embodiments above, wherein theirradiation is provided by a device described herein, for example, inany of numbered embodiments above.

216f. The device of any of numbered embodiments above, configured tofunction in a wet environment, for example, when applied to a site onthe subject comprising an aqueous liquid, for example, saline or water.

216 g. The device of any of numbered embodiments above, wherein thedevice is implanted within the subject, for example, the device is acomponent of an implantable medical device, for example, a stent, forexample, a biliary stent.

216h. The device of numbered embodiment above, wherein the device ispowered by an external power source, a battery, or an implanted powersource, for example, a battery, or an implanted power source that ischarged, for example, inductively, for example, by a charger that is notimplanted.

216i. The device of any of numbered embodiments 150-216h, wherein thedevice is configured for placement and use in a natural orifice, forexample, the mouth, ear, nose, rectum, vagina or uterus.

216j. The device of any of numbered embodiments 150-216h, wherein thedevice is configured for areas with tight bend radius of curvature, forexample, the face or distal extremities.

216k. The device of any of numbered embodiments 150-216h, wherein thedevice is configured as a glove (full or partial) for burns on the handor one or more fingers, or a skin mask for burns on the face.

216.l The device of any of numbered embodiments above, wherein thedevice comprises a material that functions as a heat sink.

216m. The device of any of numbered embodiments above, wherein thedevice comprises a cooling device, for example, a fan.

216n. The device of any of the numbered embodiments above, configured toplace the wound bed at sub-atmospheric (negative) pressure.

216o. The device of any of the numbered embodiments above, comprising anon-adherent member configured to be adjacent to the wound bed.

216p. The device of any of the numbered embodiments above, configuredsuch that an array of a plurality of light emitting modules, is disposedbetween the wound bed and a gas impermeable member which allows apressure differential between the wound bed, or the space defined by thegas impermeable membrane (the reduced pressure space), and ambientatmosphere.

216q. The device of any of the numbered embodiments 216o-216p, whereinthe non-adherent member, for example, a light emitting element, forexample, an array of a plurality of light emitting modules, comprises asynthetic rayon mesh material, a closed-cell foam, or a low surfacecoatings and materials.

216r. The device of any of the numbered embodiments 216o-216q, whereinthe non-adherent member, non-adherent member is separate from or isintegral with another element of the device, for example, a lightemitting member or array, for example, hexagonal members.

216s. The device of any of the numbered embodiments above, wherein alight emitting element, for example, an array of a plurality of lightemitting modules, has a non-adherent member, for example, a layer,disposed, for example, formed or coated on a surface that faces thewound bed.

216t. The device of any of the numbered embodiments above, comprising anarray of light emitting modules having a non-adherent surface exposed tothe wound bed, an absorbent element positioned to accept exudate orother liquid produced or present at the wound bed, and an element thatseals the device with the subject allowing for the maintenance ofnegative pressure at the wound bed.

216u. The device of any of the numbered embodiments above, comprising anelement, for example, a non-adherent member or element, configured toallow fluid transfer, for example, transfer away from the wound bed.

220. A device for providing light to the surface of a subject,comprising:

(a) an array of a plurality of light emitting modules,

wherein each module of the plurality is flexibly connected to anothermodule of the plurality; and each module of the plurality comprises

-   -   (i) a light emitting device,    -   (ii) an internally reflective layer configured to receive light        from the light emitting device,    -   (iii) a port for emission of light from the internally        reflective layer,    -   (iv) a diffusing member, and    -   (v) a polygonal perimeter,    -   wherein the array,        -   (i) is configured to conform to the surface of the subject,            and        -   (ii) comprises at least 4 modules;

(b) a light or energy source; and

(c) a connector for transmitting current or light from (b) to (a).

221. The device of numbered embodiment 220, wherein each module of theplurality comprises a hexagonal perimeter.

222. The device of any of numbered embodiments 220-221, wherein eachmodule of the plurality is configured to provide light at 0.25 to 25milliWatts/cm², for example, at the surface of the subject.

223. The device of any of numbered embodiments 220-221, wherein eachmodule of the plurality is configured to provide light having awavelength between: 380 nm and 500 nm; 390 nm and 430 nm; and 395 nm and415 nm.

224. The device of any of numbered embodiments above, wherein a modulehas a longest apex to apex distance, or a longest dimension of 5-50;10-40; 15-30; 20-25; or 22-23; millimeters.

225. The device of any of numbered embodiments above, wherein modulesare present in the array at a density of wherein modules of theplurality of modules are present at a density of 600 to 62,000; 1200 to15,000; 1700 to 6,800; 2,400 to 3,800 (20 mm); 2,900 (23 mm) to 3,200;modules/m².

226. The device of any of numbered embodiments above, wherein a majorperimeter side of a first module, for example, a hexagonal module, and amajor perimeter side of a second module, for example, a hexagonalmodule, are spaced apart, for example, spaced apart so as to optimize 1)flexibility and 2) maximize uniformity of the light filed.

227. The device of any of numbered embodiments above, wherein thedevice, for example, the module array of the device, is configured suchthat it has a bend radius of 5 mm.

228. The device of numbered embodiment above, wherein the site comprisesan arm, a leg, the neck, the torso, or the head, and the array covers atleast 25, 50, 75, or 100% of the circumference of the subject.

229. The device of any of numbered embodiments above, further comprisinga sensor.

230. The device of any of numbered embodiments above, comprising one,two, three, four, five or all of: a temperature sensor, a pH sensor, an02 sensor, a pressure sensor, a turbidity sensor, or a fluid sensor.

231. The device of any of numbered embodiments above, wherein a sensoris connected, for example, wirelessly connected, with a processor orcomputer.

232. The device of any of numbered embodiment above, responsive to asignal from the sensor, the device, or a processor or computer connectedthereto, provides a signal, for example, an alert, to another device ora person, for example, the subject or a caregiver.

233. The device of any of numbered embodiment above, responsive to asignal from the sensor, the device, or a processor or computer connectedthereto, alters an activity or property of the device.

233a. The device of any of the numbered embodiments above, configured toplace the wound bed at sub-atmospheric (negative) pressure.

233b. The device of any of the numbered embodiments above, comprising anon-adherent member configured to be adjacent to the wound bed.

233c. The device of any of the numbered embodiments above, configuredsuch that the array is disposed between the wound bed and a gasimpermeable member which allows a pressure differential between thewound bed, or the space defined by the gas impermeable membrane (thereduced pressure space), and ambient atmosphere.

233d. The device of any of numbered embodiments 233b-233c, wherein thenon-adherent member, for example, a light emitting element, for example,an array of a plurality of light emitting modules, comprises a syntheticrayon mesh material, a closed-cell foam, or a low surface coatings andmaterials.

233e. The device of any of the numbered embodiments 233b-233d, whereinthe non-adherent member, non-adherent member is separate from or isintegral with another element of the device, for example, the array.

233f. The device of any of the numbered embodiments above, wherein arrayhas a non-adherent member, for example, a layer, disposed, for example,formed or coated on a surface that faces the wound bed.

233 g. The device of any of the numbered embodiments above, the arraycomprises a non-adherent surface exposed to the wound bed, an absorbentelement positioned to accept exudate or other liquid produced or presentat the wound bed, and an element that seals the device with the subjectallowing for the maintenance of negative pressure at the wound bed.

233h. The device of any of the numbered embodiments above, comprising anelement, for example, a non-adherent member or element, configured toallow fluid transfer, for example, transfer away from the wound bed.

234. The device of any of numbered embodiments above, wherein the deviceis configured such different wavelengths of light can administered atdifferent stages of wound healing, for example, an early stage comprisesdelivering anti-microbial wavelengths and a later stage comprisesdelivering wavelengths, for example, longer wavelengths, that promotehealing.

235. A device for treating a subject, the device comprising:

a wound surface contact layer;

a rigid-flex circuit layer configured in a gapped-geometric pattern foreven distribution of light and flexibility to conform to body surfacesof a wound; and

a backing layer which, with the wound surface contact layer, isconfigured to enclose or substantially enclose the rigid-flex circuitlayer therein.

236. The device of numbered embodiment 235, wherein the rigid-flexcircuit layer is a gapped-hexagon pattern.

237. The device of numbered embodiment 236, wherein the device is 5cm×30 cm, and is configured in an offset pattern.

238. The device of numbered embodiment 236, wherein the rigid-flexcircuit layer includes a plurality of hexagon-shaped light guides.

239. The device of numbered embodiment 238, wherein each light guideincludes an LED provided along a side of the light guide.

240. The device of numbered embodiment 239, wherein the LED of eachlight guide includes an epoxy layer to protect the LED.

241. The device of numbered embodiment 238, wherein each light guideincludes an internal reflective surface feature.

242. The device of numbered embodiment 241, wherein each light guidefurther includes an optional diffuser.

243. The device of numbered embodiment 238, wherein a bottom surface ofthe device is flat and a top surface of the device includes a pattern ofmicro-dots that are layered to evenly (and uniformly) illuminate anentire light guide surface.

244. The device of 243, wherein the pattern accounts not only for theside emitting LEDs that illuminate the hexagon-shaped light guides butaccounts for other light diffusion surfaces that provide uniformityincluding a diffuser.

245. The device of 238, wherein the reflective PET layer (which could becombined with other diffuser, prismatic, or polarizing materials) isused as a means to create an effect of total internal reflection (TIR),which allows the light emitted by a side emitting LED attached to theside of the hexagon light guide to internally reflect light from oneside of the hexagon light guide to the other side.

246. The device of numbered embodiment 235, wherein the backing layerincludes a plurality of layers, including an opaque foam layer, anadhesive layer, and a plurality of PCB layers.

247. The device of numbered embodiment 246, wherein the backing layer issecured to the rigid-flex circuit layer by a plurality of adhesivelocations.

248. The device of numbered embodiment 235, wherein the wound surfacecontact layer is fabricated from white foam.

249. The device of numbered embodiment 235, further comprising a powerpack.

250. The device of numbered embodiment 249, wherein the power packincludes a rechargeable battery, a PCB control module, a power/datacable, and optionally a separate power recharge station for depletedbatteries.

251. The device of numbered embodiment 250, wherein the rechargeablebattery can be inserted and removed from a structure/housing of thepower pack.

252. The device of numbered embodiment 251, wherein, when fully charged,the rechargeable battery can last up to 8-24 hours, and, upon chargedepletion, a new fully charged battery can be inserted into thestructure/housing of the power pack.

253. The device of numbered embodiment 250, wherein the power packfurther is configured to receive power from a wall outlet.

254. The device of numbered embodiment 250, wherein the power packfurther is configured to provide warning indicators using LEDs, sound,and/or displays.

255. The device of numbered embodiment 250, wherein the power packfurther is configured to receive data from the wound dressing, which isprocessed and analyzed in the power pack.

256. The device of numbered embodiment 250, wherein the power packfurther is configured to send data to a wireless server/network torecord data and take in instructions or regiment information toindividualize treatment.

257. The device of numbered embodiment 235, further comprising a lightpatch designed and built out of fiber optics.

258. The device of numbered embodiment 257, wherein the fiber optics arein a bundle at one end thereof to receive light from an LED source andthen the light undergoes TIR through the fiber up to an opposite endthereof.

259. The device of numbered embodiment 235, further comprising a singlebody light guide including a single device (plate) that receives lightfrom multiple and overlapping light sources, for example, LEDs.

260. The device of numbered embodiment 259, wherein the single bodylight guide is 0.5 mm and can receive light from side emitting LEDs inan array attached to a flexible PCB.

261. The device of numbered embodiment 235, further comprising an LEDarray associated with the rigid-flex circuit layer.

262. The device of numbered embodiment 261, wherein the LED array isconfigured to enable flexibility in both the vertical and horizontaldirections.

263. The device of numbered embodiment 262, wherein the LED arrayincludes a plurality of hexagon-shaped light guides, each having a sizeis between 15 mm to 25 mm, with a preferable size between 20 mm and 22.5mm.

264. The device of numbered embodiment 263, wherein there is a gapbetween each hexagon-shaped light guide, the gap providing a pivot pointand flexibility between the hexagon-shaped light guides.

265. The device of numbered embodiment 264, wherein the gap is between0.75 mm and 2.50 mm for hexagon-shaped light guides ranging from 15 mmto 25 mm, respectively.

266. The device of numbered embodiment 264, wherein the gap isapproximately 1.6 mm for hexagon-shaped light guides each approximately22.5 mm.

266a. The device of any of the numbered embodiments above, configured toplace the wound bed at sub-atmospheric (negative) pressure.

266b. The device of any of the numbered embodiments above, comprising anon-adherent member configured to be adjacent to the wound bed.

266c. The device of any of the numbered embodiments above, configuredsuch that the array is disposed between the wound bed and a gasimpermeable member which allows a pressure differential between thewound bed, or the space defined by the gas impermeable membrane (thereduced pressure space), and ambient atmosphere.

266d. The device of any of numbered embodiments 266b-266c, wherein thenon-adherent member, for example the rigid-flex circuit layer, comprisesa synthetic rayon mesh material, a closed-cell foam, or a low surfacecoatings and materials.

266e. The device of any of the numbered embodiments above, comprising anelement, for example, a non-adherent member or element, configured toallow fluid transfer, for example, transfer away from the wound bed.

267. A device for providing light to the surface of a subject,comprising:

-   -   (a) an array of a plurality of light emitting modules, wherein        -   (i) the plurality comprises four light emitting modules;        -   (ii) each module of the plurality is flexibly connected to            another module of the plurality;        -   (iii) one, two, three of four of the modules of the            plurality comprise(s):            -   (A) a polygonal perimeter having 4, 5, or 6 major sides;            -   (B) a light source;            -   (C) a longest apex-to-apex dimension for a module of                5-50 millimeters; and (optionally)    -   (b) a non-adherent member configured to be adjacent to the        subject.

268. The device of embodiment 267, wherein the light source comprises alight emitting diode.

269. The device of embodiment 268, wherein the light source comprises aplurality of light emitting diodes.

270. The device of any of embodiments 267 to 268, wherein the lightsource comprises a side emitting light emitting diode.

271. The device of any of embodiments 267 to 270, further comprising anenergy source or energy conduit functionally coupled to the array of aplurality of light emitting modules.

272. The device of any of embodiments 267 to 271, wherein the polygonalperimeter is a hexagonal perimeter.

273. The device of any of embodiments 267 to 272, wherein the longestapex-to-apex of dimension of a module is 20+/−5 millimeters.

274. The device of any of embodiments 267 to 273, wherein the averagelongest apex-to-apex of dimension of the plurality of modules is 20+/−5millimeters.

275. The device of any of embodiments 267 to 274, wherein the array isconfigured to allow conformation to a surface of the body of thesubject.

276. The device of embodiment 267, wherein the array is configured toallow conformation to a surface of the body of the subject.

277. The device of any of embodiments 267 to 276, wherein each module ofthe plurality of light emitting modules comprises:

-   -   (i) an internally reflective member configured to receive light        from the light emitting diode,    -   (ii) a port for emission of light from the internally reflective        member, and    -   (iii) a diffusing member.

278. The device of any of embodiments 267 to 277 wherein the device, ora module of the plurality, emits light at a first wavelength of 675+/−15nm and at a second wavelength of 830+/−20 nm.

279. The device of embodiment 277, wherein the combination of light atthe first and the second wavelength is delivered at an irradiance1.0+/−0.5 mW/cm².

280. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at awavelength that reduces microbial levels or growth.

281. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at380-430 nm.

282. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at405+/−10 nm.

283. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at405+/−15 nm.

284. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at425+/−10 nm.

285. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at425+/−15 nm.

286. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at470+/−10 nm.

287. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at470+/−15 nm.

288. The device of any of embodiments 280 to 286, wherein light isdelivered at an irradiance of 1 mW/cm² to 10 mW/cm².

289. The device of any of embodiments 280 to 286, wherein light isdelivered at an irradiance of 2 mW/cm² to 4 mW/cm².

290. The device of any of embodiments 280 to 286, wherein light isdelivered at an irradiance of 1 mW/cm² to 4 mW/cm².

291. The device of any of embodiments 280 to 286, wherein light isdelivered at an irradiance of 2 mW/cm² to 5 mW/cm².

292. The device of any of embodiments 280 to 286, wherein light isdelivered at an irradiance of 1 mW/cm² to 5 mW/cm².

293. The device of any of embodiments 280 to 286, wherein light isdelivered at an irradiance of about 3+/−0.5 mW/cm².

294. The device of any of embodiments 280 to 286, wherein light isdelivered at an irradiance of about 3 mW/cm².

295. The device of any of embodiments 288 to 294, wherein the irradianceis the irradiance of the single recited wavelength.

296. The device of any of embodiments 288 to 294, wherein the irradianceis the combined irradiance of all wavelengths emitted.

297. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at awavelength that promotes wound healing.

298. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at650-700 nm.

299. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at675+/−10 nm.

300. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at675+/−15 nm.

301. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at675+/−20 nm.

302. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at625+/−15 nm.

303. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at690+/−15 nm.

304. The device of any of embodiments 297 to 303, wherein light isdelivered at an irradiance of 0.3 mW/cm² to 2 mW/cm².

305. The device of any of embodiments 297 to 303, wherein light isdelivered at an irradiance of 0.75+/−0.25 mW/cm².

306. The device of any of embodiments 297 to 303, wherein light isdelivered at an irradiance of 1.0+/−0.5 mW/cm².

307. The device of any of embodiments 297 to 303, wherein light isdelivered at an irradiance of about 0.75 mW/cm².

308. The device of any of embodiments 304 to 307, wherein the irradianceis the irradiance of the single recited wavelength.

309. The device of any of embodiments 304 to 307, wherein the irradianceis the combined irradiance of all wavelengths emitted.

310. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at830+/−20 nm.

311. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at810+/−20 nm.

312. The device of any of embodiments 267 to 277, wherein each module ofthe plurality of light emitting modules is configured to emit light at850+/−20 nm.

313. The device of any of embodiments 310 to 312, wherein light isdelivered at an irradiance of 0.3 mW/cm² to 2 mW/cm².

314. The device of any of embodiments 310 to 312, wherein light isdelivered at an irradiance of 0.75+/−0.25 mW/cm².

315. The device of any of embodiments 310 to 312, wherein light isdelivered at an irradiance of about 0.75 mW/cm².

316. The device of any of embodiments 313 to 315, wherein the irradianceis the irradiance of the single recited wavelength.

317. The device of any of embodiments 313 to 315, wherein the irradianceis the combined irradiance of all wavelengths emitted.

318. The device of any of embodiments 267 to 317, wherein the device, ora module of the plurality of modules, is configured to emit light of aplurality of wavelengths.

319. The device of embodiment 318, wherein the device, or a module ofthe plurality of modules, is configured to emit light at a wavelengthfrom two or all of (i) any of embodiments 280 to 287; (ii) any ofembodiments 297 to 303; and (iii) any of embodiments 310 to 312.

320. The device of embodiment 319, wherein the device, or a module ofthe plurality of modules, is configured to emit light at a wavelengthfrom (i) and (ii).

321. The device of embodiment 319, wherein the device, or a module ofthe plurality of modules, is configured to emit light at a wavelengthfrom (i) and (iii).

322. The device of embodiment 319, wherein the device, or a module ofthe plurality of modules, is configured to emit light at a wavelengthfrom (ii) and (iii).

323. A device for providing light to the surface of a subject,comprising:

-   -   (a) an array of a plurality of light emitting modules, wherein        -   (i) the plurality comprises four light emitting modules;        -   (ii) each module of the plurality is flexibly connected to            another module of the        -   plurality;        -   (iii) the modules of the plurality each comprises:            -   (A) a polygonal perimeter having 6 major sides;            -   (B) a light emitting diode;            -   (C) an internally reflective member configured to                receive light from the light emitting diode,            -   (D) a port for emission of light from the internally                reflective member, and            -   (E) a diffusing member.            -   (F) a longest apex-to-apex dimension for a module of                20+/−5 millimeters; and    -   (b) a non-adherent member configured to be adjacent to the        subject.

324. A method for providing light to a subject comprising:

-   -   providing light to the surface of a subject with a device,        comprising:        -   (a) an array of a plurality of light emitting modules,            wherein            -   (i) the plurality comprises four light emitting modules;            -   (ii) each module of the plurality is flexibly connected                to another module of the plurality;            -   (iii) one, two, three of four of the modules of the                plurality comprise(s):                -   (A) a polygonal perimeter having 4, 5, or 6 major                    sides;                -   (B) a light source;                -   (C) a longest apex-to-apex dimension for a module of                    5-50 millimeters; and (optionally)        -   (b) a non-adherent member configured to be adjacent to the            subject, thereby providing light to the subject.

325. The method of embodiment 324, wherein the device comprises thedevice of any of embodiments 267-322.

326. The method of embodiment 324, wherein the device comprises thedevice of embodiment 323.

327. The method of any of embodiments 324 to 326, wherein the subjecthas a wound and light is delivered to the wound.

328. The method of any of embodiments 324 to 327, wherein the subjecthas an acute wound such as a trauma, surgical, or burn wound and lightis delivered to the acute wound.

329. The method of any of embodiments 324 to 327, wherein the subjecthas a chronic wound such as from decubitus, pressure, diabetic, venousstasis, vascular or neurotrophic ulcers and light is delivered to thechronic would.

330. The method of any of embodiments 324 to 329, wherein the woundcomprises a microbial infection and the light delivered is sufficient toreduce the level of microbial infection.

331. The method of any of embodiments 324 to 330, wherein the lightdelivered is sufficient to promote healing of the wound.

332. The device of any of embodiments 324-331 wherein the device, or amodule of the plurality, emits light at a first wavelength of 675+/−15nm and at a second wavelength of 830+/−20 nm.

333. The device of embodiment 332, wherein the combination of light atthe first and the second wavelength is delivered at an irradiance1.0+/−0.5 mW/cm².

334. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength that reduces microbial levels or growth.

335. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 380-430 nm.

336. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−10 nm.

337. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−10 nm and at an irradiance of 2 mW/cm² to 4mW/cm².

338. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−10 nm and at an irradiance of 1 mW/cm² to 3mW/cm².

339. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−10 nm and at an irradiance of 2 mW/cm² to 4mW/cm².

340. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−10 nm and at an irradiance of 1 mW/cm² to 5mW/cm².

341. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−15 nm and at an irradiance of 2 mW/cm² to 4mW/cm².

342. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−15 nm and at an irradiance of 1 mW/cm² to 3mW/cm².

343. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−15 nm and at an irradiance of 2 mW/cm² to 4mW/cm².

344. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 405+/−15 nm and at an irradiance of 1 mW/cm² to 5mW/cm².

345. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 425+/−10 nm.

346. The method of any of embodiments 323 to 331, wherein is the lightis of a wavelength of 470+/−10 nm.

347. The method of any of embodiments 334 to 346, wherein light isdelivered at an irradiance of 1 mW/cm² to 10 mW/cm².

348. The method of any of embodiments 334 to 346, wherein light isdelivered at an irradiance of 2 mW/cm² to 4 mW/cm².

349. The method of any of embodiments 334 to 346, wherein light isdelivered at an irradiance of about 3+/−0.5 mW/cm².

350. The method of any of embodiments 334 to 346, wherein light isdelivered at an irradiance of about 3 mW/cm².

351. The method of any of embodiments 347 to 350, wherein the irradianceis the irradiance of the single recited wavelength.

352. The method of any of embodiments 347 to 350, wherein the irradianceis the combined irradiance of all wavelengths emitted.

353. The method of any of embodiments 323 to 331, wherein each module ofthe plurality of light emitting modules is configured to emit light at awavelength that promotes wound healing.

354. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 650-700 nm.

355. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 675+/−10 nm.

356. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 675+/−10 nm and at an irradiance of 0.75+/−0.25mW/cm².

357. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 675+/−15 nm and at an irradiance of 0.75+/−0.25mW/cm².

358. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 675+/−10 nm and at an irradiance of 1.0+/−0.5 mW/cm².

359. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 675+/−15 nm and at an irradiance 1.0+/−0.5 mW/cm².

360. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 830+/−20 nm and at an irradiance of 0.75+/−0.25mW/cm².

361. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 830+/−20 nm and at an irradiance of 1.0+/−0.5 mW/cm².

362. The method of any of embodiments 323 to 331, comprising irradiatingwith light of 830+/−20 nm and light of a wavelength of 675+/−15 nm andat an irradiance 1.0+/−0.5 mW/cm².

363. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 625+/−15 nm.

364. The method of any of embodiments 323 to 331, wherein the light isof a wavelength of 690+/−15 nm.

365. The method of any of embodiments 353 to 364, wherein light isdelivered at an irradiance of 0.3 mW/cm² to 2 mW/cm².

366. The method of any of embodiments 353 to 364, wherein light isdelivered at an irradiance of 0.75+/−0.25 mW/cm².

367. The method of any of embodiments 353 to 364, wherein light isdelivered at an irradiance of about 0.75 mW/cm².

368. The method of any of embodiments 360 to 367, wherein the irradianceis the irradiance of the single recited wavelength.

369. The method of any of embodiments 360 to 367, wherein the irradianceis the combined irradiance of all wavelengths emitted.

370. The method of any of embodiments 323 to 331, the light is of awavelength of 830+/−20 nm.

371. The method of any of embodiments 323 to 331, the light is of awavelength of 810+/−20 nm.

372. The method of any of embodiments 323 to 331, the light is of awavelength of 850+/−20 nm.

373. The method of any of embodiments 370 to 372, wherein light isdelivered at an irradiance of 0.3 mW/cm² to 2 mW/cm².

374. The method of any of embodiments 370 to 372, wherein light isdelivered at an irradiance of 0.75+/−0.25 mW/cm².

375. The method of any of embodiments 370 to 372, wherein light isdelivered at an irradiance of about 0.75 mW/cm².

376. The method of any of embodiments 373 to 375, wherein the irradianceis the irradiance of the single recited wavelength.

377. The method of any of embodiments 373 to 375, wherein the irradianceis the combined irradiance of all wavelengths emitted.

378. The device of any of embodiments 324 to 377, wherein the device, ora module of the plurality of modules, is configured to emit light of aplurality of wavelengths.

379. The device of embodiment 378, wherein the device, or a module ofthe plurality of modules, is configured to emit light at a wavelengthfrom two or all of (i) any of embodiments 334-347; (ii) any ofembodiments 353 to 364; and (iii) any of embodiments 370 to 372.

380. The device of embodiment 379, wherein the device, or a module ofthe plurality of modules, is configured to emit light at a wavelengthfrom (i) and (ii).

381. The device of embodiment 379, wherein the device, or a module ofthe plurality of modules, is configured to emit light at a wavelengthfrom (i) and (iii).

382. The device of embodiment 379, wherein the device, or a module ofthe plurality of modules, is configured to emit light at a wavelengthfrom (ii) and (iii).

Other Embodiments are within the following claims:

What is claimed is: 1.-20. (canceled)
 21. A device for providing lightto the surface of a subject, the device comprising: a) an array of aplurality of light emitting modules, each module of the plurality oflight emitting modules being flexibly connected to another module of theplurality of light emitting modules, and each module of the plurality oflight emitting modules being capable of emitting light, wherein thearray is configured to conform to the surface of the subject.
 22. Thedevice of claim 21, further comprising: b) a light or energy source. 23.The device of claim 22, further comprising: c) a connector fortransmitting current or light from the light or energy source to thearray of the plurality of light emitting modules.
 24. The device ofclaim 23, wherein two or more modules of the plurality of light emittingmodules are configured so as to be able to emit light simultaneously.25. The device of claim 24, wherein the device is configured to allowchanging an intensity of light across a wound bed so that some areasreceive more light than other areas responsive to a degree of woundhealing or closure.
 26. The device of claim 24, wherein two or moremodules of the plurality of light emitting modules are configured so asbe separately controllable as to varying light intensity.
 27. The deviceof claim 26, wherein one or more modules of the plurality of lightemitting modules is configured so as to be able to simultaneously emitlight at more than one wavelength.
 28. The device of claim 21, whereinthe array of modules is flexible, stretchable, or can be molded to asurface.
 29. The device of claim 28, wherein the array of modules can bebent to conform to a surface or body part of the subject, and when bentto a conforming shape, configured to retain the conforming shape. 30.The device of claim 29, wherein the array of the plurality of lightemitting modules can be bent to conform to a surface or body party ofthe subject in a plurality of dimensions.
 31. The device of claim 30,wherein each module of the plurality of light emitting modules isconfigured to provide light having a wavelength between 250 nm and 500nm, and light having a wavelength between 280 nm and 315 nm.
 32. Thedevice of claim 30, wherein each module of the plurality of lightemitting modules is configured to provide light at 0.25 to 25milliWatts/cm² at a surface of the subject.
 33. The device of claim 30,wherein each module of the plurality of light emitting modules isconfigured to provide light having a wavelength between: 380 nm and 500nm; 390 nm and 430 nm; and 395 nm and 415 nm.
 34. The device of claim30, wherein each module of the plurality of light emitting modules isconfigured to provide light having a wavelength between: 625-690 nm forwound healing.
 35. The device of claim 21, wherein each module of theplurality of light emitting modules comprises a first light emittingdevice which emits light at a first wavelength and a second lightemitting device that emits light at a second wavelength.
 36. The deviceof claim 21, wherein each module of the plurality of light emittingmodules comprises a polygonal perimeter.
 37. The device of claim 36,wherein each module of the plurality of light emitting modules comprisesa hexagonal perimeter.
 38. The device of claim 37, wherein a module ofthe plurality of light emitting modules comprises a layer configured toreceive light from an edge of the hexagonal perimeter, the edge beinginternally reflective, and comprises one or a plurality of ports foremission of light.
 39. The device of claim 38, further comprising adiffusing member, which results in a substantially uniform level ofirradiation to the subject.
 40. The device of claim 21, wherein thearray comprises: a flexible backing member including a layer of foam,which covers or contacts a module of the plurality of light emittingmodules of the array; and an adhesive member disposed between thebacking member and a module of the plurality of light emitting modules.